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Microdeletions of Xp22.3 can result in contiguous gene syndromes, showing the variable association of apparently unrelated clinical manifestations such as ichthyosis, chondrodysplasia punctata, hypogonadotropic hypogonadism, anosmia, ocular albinism, short stature and mental retardation. We report on a boy with ichthyosis, dysmorphic features and mental retardation with ADHD. The patient was born at term after a pregnancy complicated by threatened abortion; decreased fetal movements and low estriol serum levels were reported during the last trimester. The boy was referred to us at the age of 13 years. He presented with aggressive and hyperactive behavior. He had dry hair, a flat face, bilateral lens opacities, a small nose with hypoplastic tip, alae nasi and nares, a high-arched palate with a very small cleft, mixed dentition with 7 unerupted permanent teeth, left sensorineural and right mixed hearing loss with a calcified plaque of the tympanic membrane, marked shortness of terminal phalanges of hands and feet, ichthyosis of trunk and limbs. The genomic interval between AFM248th5 and KAL1 was investigated. PCR analysis showed a deletion in Xp22.3, with the distal breakpoint between the marker AFM248th5 and PABX and the proximal one between DXS278 and KAL1 . Array-CGH and FISH analysis confirmed the interstitial deletion (of about 5.5 Mb) and refined the breakpoints. We discuss the phenotype of our patient in relationship to the deleted segment and the possibility of mental retardation and ADHD genes in the region.

Inborn defects of cholesterol biosynthesis are a group of metabolic disorders presenting with mental retardation and multiple congenital anomalies (MCA/MR syndromes). Functional and structural liver involvement has been reported as a rare (2.5-6%) complication of the Smith-Lemli-Opitz syndrome (SLOS) and it has not been fully characterized. Here, we report on a long-term follow-up study of four patients with SLOS, and one case with lathosterolosis who presented with liver disease and underwent an extensive diagnostic work-up. Reports of liver involvement in cholesterol biosynthesis defects are reviewed. Two main different patterns of liver involvement emerged: progressive cholestasis, and stable isolated hypertransaminasemia. In our series, the first pattern was found in two patients with SLOS and one with lathosterolosis, and the second in two SLOS cases. Cholestasis was associated with early lethality and normal serum gamma-glutamyl-transferase (GGT) levels in SLOS, while possible prolonged survival and high GGT levels were seen in lathosterolosis. Hepatic fibrosis was present in both conditions. Liver biopsy performed in one of our SLOS patients with isolated hypertransaminasemia, showed only mild hydropic degeneration of the hepatocytes. The presence of liver involvement in 16% of the SLOS patients diagnosed at our Center suggests that this complication might have been underestimated in previously reported cases, possibly overshadowed by the severity of multiple malformations. Fetal hepatopathy, cholestasis, and isolated hypertransaminasemia can occur also in other disorders of cholesterol biosynthesis, such as mevalonic aciduria, desmosterolosis, Conradi-Hunermann syndrome, Greenberg dysplasia, and Pelger-Huet homozygosity syndrome. This group of inherited disorders should be considered in the differential diagnosis of patients presenting with liver disease associated with developmental delay and/or multiple malformations. Periodic liver function evaluations are recommended in these patients.

Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Glycogen storage disease type 1b (GSD-1b) is an autosomal-recessive disease caused by mutation of glucose-6–phosphate transporter and characterized by altered glycogen/glucose homeostasis. A higher frequency of autoimmune diseases has been observed in GSD-1b patients, but the molecular determinants leading to this phenomenon remain unknown. To address this question, we investigated the effect of glucose-6–phosphate transporter mutation on immune cell homeostasis and CD4+ T cell functions. In GSD-1b subjects, we found lymphopenia and a reduced capacity of T cells to engage glycolysis upon TCR stimulation. These phenomena associated with reduced expression of the FOXP3 transcription factor, lower suppressive function in peripheral CD4+CD25+FOXP3+ regulatory T cells, and an impaired capacity of CD4+CD25− conventional T cells to induce expression of FOXP3 after suboptimal TCR stimulation. These data unveil the metabolic determinant leading to an increased autoimmunity risk in GSD-1b patients.

Growing evidence indicates that inherited metabolic diseases are increasingly being recognised. Life expectancy for many patients is progressively improving because new therapeutic strategies are available. Because most inherited metabolic diseases are systemic disorders, virtually all organs may be involved. Respiratory disease complicates the management of several inherited metabolic diseases, either at presentation or as late-onset features. This review will describe the most exemplary respiratory manifestations of inherited metabolic diseases in childhood and adulthood. Since airways disease worsens the morbidity of many inherited metabolic disorders, leading to increased hospitalisations, mortality and overall healthcare costs, respiratory manifestations of inherited metabolic diseases need to be carefully recognised and treated. All patients with inherited metabolic disease and suspected airway disease should undergo a detailed diagnostic work-up. Current treatments for several inherited metabolic diseases (including enzyme replacement therapy, substrate reduction, bone marrow transplantation, or even more innovative strategies such as pharmacological chaperone or gene therapies) may provide significant benefits for associated respiratory disease. The integration of several specialists dedicated to airway disease management in a multidisciplinary team is essential to provide the most appropriate care to children and adults with inherited metabolic disease.

The region 21q22 is considered crucial for the pathogenesis of both Down syndrome (DS) and the partial monosomy 21q syndrome. Haploinsufficiency of the RUNX-1 gene, mapping at 21q22 is responsible for a platelet disorder and causes predisposition to myelodysplastic syndrome (MDS). We describe a 3-year-old girl with mental retardation, congenital heart malformation, and subtle dysmorphic facial features. The patient developed thrombocytopenia when she was 2 years old. Bone marrow smear led to the diagnosis of myelodysplasia. Prenatal karyotyping had shown chromosome 21 pericentric inversion. Postnatally the array-CGH revealed duplication at bands 21q11.2-21q21.1 and a simultaneous deletion involving the region 21q22.13-21q22.3. RUNX-1 mRNA levels analyzed in patient's skin fibroblasts were reduced. In this child the monosomy of the region 21q22 likely had the main role in determining the phenotype. Although the RUNX-1 gene is localized outside the deleted region, we speculate that RUNX-1 reduced expression, is probably due to the deletion of regulatory factors and caused the hematologic disorder in the patient. The present report underlines also the importance of array-CGH in characterizing patients with a complex phenotype.

Introduction Glycogen storage disease type III (GSDIII) is an inborn error of carbohydrate metabolism caused by deficient activity of glycogen debranching enzyme (GDE). It is characterized by liver, cardiac muscle and skeletal muscle involvement. The presence of systemic complications such as growth retardation, ovarian polycystosis, diabetes mellitus and osteopenia/osteoporosis has been reported. The pathogenesis of osteopenia/osteoporosis is still unclear. Objectives The aim of the current study was to evaluate the bone mineral density (BMD) in GSDIII patients and the role of metabolic and endocrine factors and physical activity on bone status. Methods Nine GSDIII patients were enrolled (age 2–20 years) and compared to eighteen age and sex matched controls. BMD was evaluated by Dual-emission-X-ray absorptiometry (DXA) and Quantitative ultrasound (QUS). Clinical and biochemical parameters of endocrine system function and bone metabolism were analyzed. Serum levels of the metabolic control markers were evaluated. Physical activity was evaluated by administering the International Physical Activity Questionnaire (IPAQ). Results GSDIII patients showed reduced BMD detected at both DXA and QUS, decreased serum levels of IGF-1, free IGF-1, insulin, calcitonin, osteocalcin (OC) and increased serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX). IGF-1 serum levels inversely correlated with AST and ALT serum levels. DXA Z-score inversely correlated with cholesterol and triglycerides serum levels and directly correlated with IGF-1/IGFBP3 molar ratio. No difference in physical activity was observed between GSDIII patients and controls. Discussion Our data confirm the presence of reduced BMD in GSDIII. On the basis of the results, we hypothesized that metabolic imbalance could be the key factor leading to osteopenia, acting through different mechanisms: chronic hyperlipidemia, reduced IGF-1, Insulin and OC serum levels. Thus, the mechanism of osteopenia/osteoporosis in GSDIII is probably multifactorial and we speculate on the factors involved in its pathogenesis.

International audience; Disorders of post-squalene cholesterol biosynthesis are inborn errors of metabolism characterised by multiple congenital abnormalities, including significant skeletal involvement. The most frequent and best-characterised example is the Smith-Lemli-Opitz syndrome. Nine other disorders are known, namely autosomal-recessive Antley-Bixler syndrome, Greenberg dysplasia, X-linked dominant chondrodysplasia punctata, X-linked recessive male emopamil-binding protein deficiency, CHILD syndrome, CK syndrome, sterol C4 methyloxidase-like deficiency, desmosterolosis and lathosterolosis. This study provides an overview of the radiologic features observed in these diseases. A common pattern of limb abnormalities is recognisable, including polydactyly, which is typically post-axial and rarely interdigital and can involve all four limbs, and syndactyly of the toes. Chondrodysplasia punctata is specifically associated with a subgroup of disorders of cholesterol biosynthesis (Greenberg dysplasia, CHILD syndrome, X-linked dominant chondrodysplasia punctata, male emopamil-binding protein deficiency). The possible occurrence of epiphyseal stippling in the Smith-Lemli-Opitz syndrome, initially reported, does not appear to be confirmed. Stippling is also associated with other congenital disorders such as chromosomal abnormalities, brachytelephalangic chondrodysplasia punctata (X-linked recessive chondrodysplasia punctata, disruptions of vitamin K metabolism, maternal autoimmune diseases), rhizomelic chondrodysplasia punctata (peroxisomal disorders) and lysosomal storage disorders. In the differential diagnosis of epiphyseal stippling, a moth-eaten appearance of bones, asymmetry, or presence of a common pattern of limb abnormalities indicate inborn errors of cholesterol biosynthesis. We highlight the specific differentiating radiologic features of disorders of post-squalene cholesterol biosynthesis.

Background: In GSDIa, glucose 6-phosphate (G6P) accumulates in the endoplasmic reticulum (ER); in GSDIb, G6P levels are reduced in ER. G6P availability directly modulates the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an ER-bound enzyme playing a key role in the development of the metabolic syndrome (MS). Objective: To evaluate the prevalence of MS and Insulin Resistance (IR) in GSDIa and GSDIb patients. Patients and Methods: This was a prospective study. All the enrolled patients were followed at the Department of Pediatrics "Federico II" University of Naples for 10 years. Clinical and biochemical parameters of MS and the presence of IR were recorded. The results were correlated with the biochemical parameters of GSDI-related metabolic control. 10 GSDIa patient (median age 12.10 ± 1.50), 7 GSDIb patients (median age 14.90 ± 2.20 were enrolled in the study. They were compared to 20 and 14 age and sex matched controls, respectively. 10 GSDIa patients (median age 24.60 ± 1.50) and 6 GSDIb patients (median age 25.10 ± 2.00) completed the 10-year-follow-up. At the end of the study the patients' data were compared to 10 and 6 age and sex matched controls, respectively. Results: At study entry, 20 % GSDIa patients had MS and 80 % showed 2 criteria for MS. GSDIa patients showed higher HOMA-IR than controls and GSDIb patients (p < 0.001, p < 0.05), respectively. Baseline ISI was lower in GSDIa than controls (p < 0.001). QUICKI was significantly lower in GSDIa than in controls (p < 0.001). At the end of the study 70 % of GSDIa patients had MS and 30 % showed 2 criteria for MS. HOMA-IR was higher in GSDIa than controls (p < 0.01). Baseline ISI was higher in GSDIb than controls (p < 0.005) and GSD1a (p < 0.05). QUICKI was lower in GSD1a patients than in controls (p < 0.03). VAI was higher in GSDIa patients than controls (p < 0.001) and GSDIb patients (p = 0.002). Conclusions: Our data showed high prevalence of IR and MS in GSDIa patients. We speculate a possible role of 11βHSD1 modulation by G6P availability. We suggest a routine metabolic assessment in GSDIa patients.

Background Twenty-five patients with Niemann Pick disease type C (age range: 7 months to 44 years) were enrolled in an Italian independent multicenter trial and treated with miglustat for periods from 48 to 96 months. Methods Based on the age at onset of neurological manifestations patients’ phenotypes were classified as: adult (n = 6), juvenile (n = 9), late infantile (n = 6), early infantile (n = 2). Two patients had an exclusively visceral phenotype. We clinically evaluated patients’ neurological involvement, giving a score of severity ranging from 0 (best) to 3 (worst) for gait abnormalities, dystonia, dysmetria, dysarthria, and developmental delay/cognitive impairment, and from 0 to 4 for dysphagia. We calculated a mean composite severity score transforming the original scores proportionally to range from 0 to 1 to summarize the clinical picture of patients and monitor their clinical course. Results We compared the results after 24 months of treatment in 23 patients showing neurological manifestations. Stabilization or improvement of all parameters was observed in the majority of patients. With the exception of developmental delay/cognitive impairment, these results persisted after 48–96 months in 41 – 55% of the patients (dystonia: 55%, dysarthria: 50%, gait abnormalities: 43%, dysmetria: 41%, respectively). After 24 months of therapy the majority of the evaluable patients (n = 20), demonstrated a stabilization or improvement in the ability to swallow four substances of different consistency (water: 65%, purée: 58%, little pasta: 60%, biscuit: 55%). These results persisted after 48–96 months in 40-50% of patients, with the exception of water swallowing. Stabilization or improvement of the composite severity score was detected in the majority (57%) of 7 patients who were treated early (within 3.5 years from onset) and rarely in patients who received treatment later. Conclusions The results of this study suggest that miglustat treatment can improve or stabilize neurological manifestations, at least for a period of time; the severity of clinical conditions at the beginning of treatment can influence the rate of disease progression. This conclusion applies particularly to patients with juvenile or adult onset of the disease. Trial registration EudraCT number 2006-005842-35 Electronic supplementary material The online version of this article (doi:10.1186/s13023-015-0240-y) contains supplementary material, which is available to authorized users.

We report a 3-year-old Italian patient with the hyperornithinaemia, hyperammonaemia, homocitrullinuria (HHH) syndrome who presented with neurological deterioration after an intercurrent infection. Hyperammonaemia, coagulopathy and moderate hypertransaminasaemia were detected on hospital admission. Severe hepatocellular necrosis with hypertransaminasaemia (aspartate aminotransferase 20,000 UI/L, alanine aminotransferase 18,400 UI/L) and coagulopathy (PT < 5%) rapidly developed within few days, prompting evaluation for liver transplantation. A protein-restricted diet and arginine supplementation were immediately started, with a rapid improvement of the patient's neurological conditions and normalization of liver function tests and blood ammonia. The diagnosis of HHH syndrome was based on the presence of the typical metabolic abnormalities. Molecular analysis of the SLC25A15 gene showed that the patient was heterozygous for two novel mutations (G113C and M273K). The diagnosis of HHH syndrome should be considered in patients with fulminant hepatitis-like presentations. Early identification and treatment of these patients can be life-saving and can avoid liver transplantation.

The '13q-' syndrome shows widely variable manifestations. Investigation of the involvement of different tissues has never been reported in patients with 13q- syndrome previously. We describe a patient with mosaicism for del(13q) and clinical features of 13q- syndrome. The mother of the patient was professionally exposed to aniline colorants and glue components during the whole pregnancy. The patient had dysmorphic features, skeletal anomalies and brain malformations with agenesis of the corpus callosum, vermian hypoplasia and IVth ventricular system abnormalities. Eye examination revealed chorioretinal coloboma and irregular dispersion of retinal pigment in the right eye. The karyotype analyses and the molecular studies performed on peripheral lymphocytes, oral swab and cells of urinary tract were normal whereas a deletion of the long arm of chromosome 13 (13q13.2) was found in skin fibroblasts and in hair cells. We hypothesized that the 13q deletion arose during the third week after conception possibly due to a teratogeniceffect and that tissue of mesodermal and ectodermal origin are involved. We suggest analysing a fibroblast karyotype when a diagnosis of 13q- syndrome is suspected on clinical ground. The role of teratogens in causing this type of mosaic chromosome abnormality also warrants further investigation.

Summary Background The efficacy of ACE-inhibitors in decreasing microalbuminuria and proteinuria has been reported in a few patients with glycogen storage disease type 1 (GSD1); however, no case-control study has ever been published. Aim The aim of the current study was to evaluate the efficacy of ACE-inhibitors in reducing glomerular hyperfiltration, microalbuminuria and proteinuria, and in delaying the progression of renal damage. Patients and methods Ninety-five patients (median age at the time of the study: 14·5 years) were enrolled from nine Italian referral centres for metabolic diseases. A retrospective study of a 10-year follow-up was conducted in order to compare the evolution of these parameters in treated patients with those who were not treated with ACE-inhibitors. Results A significant and progressive decrease of glomerular filtration rate was observed in treated patients vs. those who were not treated with ACE-inhibitors (P

OBJECTIVE: To investigate brain morphology and function in patients with glycogen storage disease type I (GSDI). STUDY DESIGN: Nineteen patients (13 females and 6 males, aged 0.9-22.6 years) and 38 sex- and age-matched controls entered the study. Neurological examinations, psychometric tests (IQ, tests of performance and verbal abilities), standard electroencephalogram (EEG), somatosensory (SEPs), visual (VEPs), and brain-stem auditory evoked potentials (BAEPs), and brain magnetic resonance imaging (MRI) were performed. RESULTS: The results of tests of performance ability were lower in patients than in controls (P

Background: The management of subclinical hypothyroidism (SH) is still controversial, as the benefit to risk ratio of prolonged L-thyroxine therapy is not clear cut. Some authors have shown abnormalities of myocardial function and structure in adults with SH, which could be reversed by L-thyroxine therapy. As SH frequently affects children with Down's syndrome (DS), and almost one half of these are affected by congenital heart disease, a concomitant SH related impairment of cardiac function might further compromise their clinical condition. Aims: To establish whether SH influences myocardial structure and function in children with DS. Methods: Sixteen children with DS and untreated SH and 25 matched euthyroid controls with DS underwent echocardiographic analysis of left ventricular mechanics and tissue characterisation. Results: None of the 16 patients had myocardial impairment. Conclusion: Results suggest that children with DS who have SH are not at risk of cardiac disease. Clinicians should consider these data in the management of SH, as the benefit to risk ratio of prolonged L-thyroxine therapy is not clear cut.

A patient with a multiple congenital anomalies/mental retardation (MCA/MR) syndrome had an unbalanced translocation (3;5)(q26.1;p14), causing partial 5p monosomy and partial 3q trisomy. The phenotype observed in this patient results from the combination of those described in the isolated dup(3q) and del(5p) syndromes. Some clinical features of this patient are shared by the Smith-Lemli-Opitz syndrome (SLOS), a well-known MCA/MR syndrome due to the deficiency of 7-dehydrocholesterol reductase (DHCR7). We review the previously reported cases of chromosomal anomalies with clinical features suggesting SLOS.

Aim Dysphagia is a known complication in Pompe Disease (PD), a severe metabolic myopathy due to alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) with alglucosidase alfa is the only approved therapy for PD. Presently no data are available on the effects of ERT on dysphagia in PD patients. The aim of this work is to evaluate the course of this complication in a 6 years old boy affected by PD after treatment with ERT. Methods Dysphagia was assessed by Videofluoroscopic Swallowing Study (VFSS) at baseline, before the start of ERT and after 36 months of therapy. We used the Dysphagia Severity Rating Scale (DSS) to define the severity grade of dysphagia. Results VFSS performed at baseline revealed complete incoordination of oral stage swallowing which was classified as a grade 1 dysphagia according to DSS. After 36 months of treatment VFSS revealed normal swallowing, classified as grade 0 by DSS. Conclusion Our results suggest that ERT is effective in improving dysphagia. VFSS may be a useful tool to investigate and monitor swallowing disorders in patients affected by PD.

Background: Glycogen storage disease type 1 (GSD1) is a rare and genetically heterogeneous metabolic defect of gluconeogenesis due to mutations of either the G6PC gene (GSD1a) or the SLC37A4 gene (GSD1b). Osteopenia is a known complication of GSD1. Objectives: The aim of this study was to investigate the effects of poor metabolic control and/or use of GSD1-specific treatments on bone mineral density (BMD) and metabolism in GSD1 patients. Methods: In a multicenter, cross-sectional case-control study, we studied 38 GSD1 (29 GSD1a and 9 GSD1b) patients. Clinical, biochemical and instrumental parameters indicative of bone metabolism were analyzed; BMD was evaluated by dual-emission X-ray absorptiometry and quantitative ultrasound. Results: Both GSD1a and GSD1b patients showed reduced BMD compared with age-matched controls. In GSD1a patients, these abnormalities correlated with compliance to diet and biochemical indicators of metabolic control. In GSD1b patients, BMD correlated with the age at first administration and the duration of granulocyte colony-stimulating factor (G-CSF) therapy. Conclusions: Our data indicate that good metabolic control and compliance with diet are highly recommended to improve bone metabolism in GSD1a patients. GSD1b patients on G-CSF treatment should be carefully monitored for the risk of osteopenia/osteoporosis.

Ehlers Danlos syndrome (EDS) athrocalasia type (type VII), is characterized by joint hypermobility, skin hyperextensibility and tissue fragility. No heart involvement has been reported. Two forms have been described: type VII A and VII B. The abnormally processed collagen α2(I) and the skipping of the exon 6 in COL1A2 gene are typically detected in EDS type VII B. We describe a seven-year old female, with a phenotype consistent with EDS type VII B and a diagnosis further confirmed by biochemical and molecular analyses. Cardiac ultrasound showed normal data in the first year of life. When she was 5 years old, the patient developed mitral valve regurgitation, and aortic and tricuspidal insufficiency at 7 years of age. To our knowledge, this is the first report of cardiac valvular involvement in EDS VII B. This feature probably has been underreported for the limited follow-up of the patients. Echocardiography might be warranted in the clinical assessment of EDS VII patients.

Fabry disease (FD) is an X-linked inherited disease due to alpha-galactosidase A (alpha-Gal A) deficiency and characterized by lysosomal storage of globotriaosylceramide (Gb3) and related neutral glycosphingolipids. Storage of these substrates results in multisystem manifestations, including renal failure, cardiomyopathy, premature myocardial infarctions, stroke, chronic neuronopathic pain, gastrointestinal disturbances, and skin angiokeratoma. Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A (rh-alpha-Gal A) is now available for the treatment of FD and in most patients results in clinical improvement or stabilization. However, ERT efficacy may vary in different tissues and its long-term effects remain to be defined. As a strategy to improve the efficacy of ERT, we tested the combination of rh-alpha-Gal A with the chaperone molecule 1-deoxynojirimycin (DGJ) in cultured FD fibroblasts with negligible residual enzyme activity. Compared to the effects of rh-alpha-Gal A alone, co-administration of DGJ and rh-alpha-Gal A resulted in better correction (4.8 to 16.9-fold) of intracellular alpha-Gal A activity, and increased amounts of the enzyme within the lysosomal compartment. The clearance of lyso-Gb3, one of the substrates stored in FD and a potent inhibitor of alpha-Gal A, was also significantly improved with the co-administration of DGJ and rh-alpha-Gal A. This study provides additional evidence for a synergistic effect between ERT and pharmacological chaperone therapy and supports the idea that the efficacy of combination protocols may be superior to ERT alone.

Haploinsufficiency of a region located distal to 10p14 designated HDR1, is responsible for hypoparathyroidism, sensorineural deafness, and renal anomalies (HDR syndrome). Haploinsufficiency of a more proximal region, located on 10p13-10p14, designated as DGCR2 is associated with congenital heart defects and thymus hypoplasia/aplasia or T cell defect. We describe a patient showing facial dysmorphisms, delayed psychomotor development and bilateral sensorineural hearing loss and carrying a 10p14 deletion, the smallest deletion found in the literature so far. Our patient, carrying a partial deletion of the DGCR2 region and of the HDR1 region, including the GATA3 gene, showed, unexpectedly, only few of the clinical features of DiGeorge 2 syndrome (psychomotor retardation, palpebral ptosis, epicanthic folds, anteverted nares, cryptorchidism, hand/foot abnormalities) and did not show other typical signs, such as cardiac defect, cleft palate, and abnormal T cell levels. Of the three characteristic features of the HDR syndrome, our patient had only sensorineural deafness. On the basis of the revision of the other cases reported in the literature with a deletion including the 10p14 region, we suggest that GATA3 haploinsufficiency, although not recorded for each patient, is responsible for deafness. The present case shows that even this small 10p deletion is responsible for a specific phenotype. We also underline the importance of CGH-array, in order to obtain a more precise physical mapping of the 10p deletions and an accurate genotype-phenotype correlation. (C) 2012 Wiley Periodicals, Inc.

Purpose evaluate the psychomotor evolution of a child with Multiple acyl-CoA dehydrogenase deficiency after treatment with L-carnitine, ubiquinone and riboflavin. Methods an assessment of psychomotor development was performed before the start of farmacological treatment using the Assessment Scale of Mental Development Griffiths (GMDS-R, 0–2 years). The same assessment was performed after a month and after six months of treatment to evaluate the possible benefits of treatment. Results we noticed a quick and dramatic improvement in muscular tone and motor performances after pharmacological treatment. We also observed a substantial improvement in the personal/social and hearing/language areas, suggesting the presence of intellectual/cognitive improvement. The clinical improvement correlated with the biochemical response. Conclusion In our patient early therapy resulted in a optimal response in psychomotor development, motor function and muscole hypotonia. Evaluation with GMDS-R, a simple, non-invasive and multidimensional tool, represents a useful instrument to monitor the clinical response to treatment.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder characterized by defective intracellular lipid trafficking, with secondary accumulation of free cholesterol, sphingosine, and glycosphingolipids. NPC is clinically characterized by a wide spectrum of manifestations with progressive visceral and neurological involvement, including dysphagia. Neurological manifestations represent the most debilitating findings. Swallowing impairment is a frequent cause of morbidity and disability in NPC patients and progressive dysphagia may be considered a marker of neurological progression. Recently substrate reduction therapy with miglustat has been proposed for the treatment of neurological manifestations in NPC patients. This observational study reports on the long-term use of miglustat in four pediatric patients with NPC and shows the efficacy of the treatment to improve or prevent dysphagia, and persistence after 3 years of treatment or more. We used a videofluoroscopic analysis of liquid barium swallowing to provide additional information on patterns of impairment of the swallowing mechanism and to detect aspiration. In three patients showing dysphagia and aspiration we observed the improvement of the swallowing function and the sustained absence of barium aspiration in the airways after miglustat treatment, while the patient with normal swallowing function at baseline did not show any deterioration. We suggest that the videofluoroscopic study of swallowing should be routinely used to monitor the effects of treatment on swallowing ability in NPC patients.

Pompe disease (PD) is a metabolic myopathy caused by the deficiency of the lysosomal hydrolase acid α-glucosidase (GAA) and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the attenuated intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is at present the only approved treatment for PD, in addition to supportive and physical therapies. However, ERT shows limited efficacy in some patients and does not completely correct the disease phenotype. Recently, an improved knowledge of PD pathophysiology has provided clues to explain the limitations of ERT. A mechanical effect of lysosomal inclusions on muscle contractility has been proposed as a key factor of disease resulting in a severe loss of contractility. In addition, it has been shown that secondary abnormalities of housekeeping cellular functions, such as autophagy, have an important role in the pathogenesis of cell damage in PD. Abnormalities of intra-cellular trafficking of vesicles and membrane-bound proteins, such as the cation-independent mannose-6-phosphate receptor, may be deleterious for the efficacy of ERT. At present, new therapeutic strategies, in addition to ERT, are under investigation. An emerging strategy for the treatment of PD is pharmacological chaperone therapy, based on the use of chaperone molecules that assist the folding of mutated enzymes and improve their stability and lysosomal trafficking. Pre-clinical studies demonstrated a synergistic effect of pharmacological chaperones and ERT. Other approaches, also in a pre-clinical stage, include substrate reduction and gene therapy.

International audience; OBJECTIVE: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations. METHODS: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family. RESULTS: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1). CONCLUSIONS: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.

Fourteen patients (six males, eight females; mean age, 20 years) with homocystinuria due to homozygous cystathionine-beta-synthase (CBS) deficiency, underwent a vascular examination. Fourteen heterozygotes (seven males, seven females; mean age, 46 years), including 12 parents and one daughter of homozygotes (obligate heterozygotes), and one sister of a homozygote (with low enzyme activity as evaluated in vitro), were also examined. Homozygotes and heterozygotes were compared with two separate control groups of different age (mean age, 20 and 43 years, respectively). Ankle/arm systolic pressure index (by continuous-wave Doppler) was, on average, lower in homozygotes (P less than .01) and heterozygotes (P less than .05) as compared with the controls. An ankle/arm index less than 0.97 and suggesting flow-reducing arterial lesions was found in six (21%) lower limbs of homozygotes versus zero in controls (P less than .05). Echo Doppler (Duplex Scanner) abnormalities, indicating early, non-flow-reducing lesions of iliac arteries were more frequent in homozygotes (seven wall abnormalities or stenoses less than 15%) than in young controls (P less than .05). The corresponding figures for heterozygotes were seven wall abnormalities or stenoses (1% to 15% and one stenosis 16% to 50%) (P less than .01 v middle-aged controls). Early lesions (three wall abnormalities or stenoses less than 15%, three stenoses 16% to 50%) were detected in six (23%) internal carotids of heterozygotes versus three (3%) of corresponding controls (P less than .05). Technical limitations precluded the accurate detection of early lesions in the internal carotid arteries of young homozygotes and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Pompe disease is a rare autosomal recessive myopathy due to the deficiency of lysosomal acid alpha-glucosidase. Clinical phenotypes range from the severe classic infantile form (hypotonia and hypertrophic cardiomyopathy), to milder late onset forms (skeletal myopathy and absence of significant heart involvement). Enzyme replacement therapy with recombinant human alpha-glucosidase derived from either rabbit milk or Chinese hamster ovary cells has been introduced and is undergoing clinical trials. Reported is a long-term follow-up of 3 Pompe patients presenting without cardiomyopathy, treated with recombinant human alpha-glucosidase derived from Chinese hamster ovary cells. This study suggests that enzyme replacement therapy can lead to significant motor and respiratory improvement in the subgroup of patients who start the therapy before extensive muscle damage has occurred. The recombinant enzyme derived from Chinese hamster ovary cells, administered at doses significantly higher than previously reported, appears to have the same safety as the drug derived from rabbit milk.

In mucopolysaccharidoses, upper airway obstruction has multiple causative factors and progressive respiratory disease may severely affect morbidity and mortality. In a cross-sectional study over 2 years we evaluated upper airway obstructive disease through overnight polysomnography, upper airway computed tomography and nasal endoscopy in 5 children and 6 adults with mucopolysaccharidoses of various types. Measurements of apnoea and apnoea-hypopnoea index, arousal index, and sleep efficiency were obtained through polysomnography. Retropalatal and retroglossal spaces were calculated through computed tomography, and the degree of adenoid hypertrophy was assessed through endoscopy. Apnoea index and apnoea-hypopnoea index were significantly higher in children than in adults with mucopolysaccharidoses (p = 0.03 and p = 0.03, respectively). Compared to healthy controls, retropalatal and retroglossal spaces were significantly smaller in children (p = 0.03 and p = 0.004, respectively) or adults with mucopolysaccharidoses (p = 0.004 and p = 0.004, respectively). All subjects had adenoid hypertrophy causing first-degree (36%) or second-degree (64%) obstruction at endoscopy. Overnight polysomnography, upper airway computed tomography and nasal endoscopy are useful tools for diagnosing obstructive sleep apnoea syndrome in mucopolysaccharidoses, and identifying the site and severity of airway obstruction.

PURPOSE: We present a case-control study of seven polymorphisms of six genes involved in homocysteine/folate pathway as risk factors for Down syndrome. Gene-gene/allele-allele interactions, haplotype analysis and the association with age at conception were also evaluated. METHODS: We investigated 94 Down syndrome-mothers and 264 control-women from Campania, Italy. RESULTS: Increased risk of Down syndrome was associated with the methylenetetrahydrofolate reductase (MTHFR) 1298C allele (OR 1.46; 95% CI 1.02-2.10), the MTHFR 1298CC genotype (OR 2.29; 95% CI 1.06-4.96), the reduced-folate-carrier1 (RFC1) 80G allele (1.48; 95% CI 1.05-2.10) and the RFC1 80 GG genotype (OR 2.05; 95% CI 1.03-4.07). Significant associations were found between maternal age at conception > or = 34 years and either the MTHFR 1298C or the RFC 180G alleles. Positive interactions were found for the following genotype-pairs: MTHFR 677TT and 1298CC/CA, 1298CC/CA and RFC1 80 GG/GA, RFC1 80 GG and methylenetetrahydrofolate-dehydrogenase 1958 AA. The 677-1298 T-C haplotype at the MTHFR locus was also a risk factor for Down syndrome (P = 0.0022). The methionine-synthase-reductase A66G, the methionine-synthase A2756G and the cystathionine-beta-synthase 844ins68 polymorphisms were not associated with increased risk of Down syndrome. CONCLUSION: These results point to a role of maternal polymorphisms of homocysteine/folate pathway as risk factors for Down syndrome.

The oligosaccharidoses are a group of lysosomal storage disorders characterized by defects of glycoprotein degradation due to the deficiency of specific lysosomal enzymes (Fig. 19.1). All are inherited as autosomal recessive traits.

We studied the genotype/phenotype correlation in a cohort of glycogen storage disease type (GSD) 1b patients. A total of 25 GSD1b patients, 13 females and 12 males, age range: 4.3-28.4 years, mean:14.6+/-6.8 years; median: 15 years, representing the entire case load of Italian GSD1b patients, were enrolled in the study. Molecular analysis of the glucose 6-phosphate translocase (G6PT1) gene was performed in all patients. We analysed the presence of a correlation among both the clinical features associated with GSD1b (neutropenia, frequency of admission to the hospital for severe infections) and the presence of systemic complications (liver adenomas, nephropathy, bone mineral density defect, polycystic ovaries, short stature, inflammatory bowel disease) and the mutations detected in each patient. Nine patients were homozygous or compound heterozygous for mutations causing stop codons. In particular, three patients were homozygous for the same mutation (400X); of these patients, one showed chronic neutropenia with severe and frequent infections and severe inflammatory bowel disease, another patient cyclic neutropenia associated with rare bacterial infections and mild bowel involvement and the last one normal neutrophil count. Two patients were homozygous for the mutation 128X; one of these patients did not show neutropenia, whereas the other one had severe neutropenia needing frequent hospital admission and was under granulocyte-colony stimulating factor treatment. In three patients no mutations were detected. CONCLUSION: No correlation was found between individual mutations and the presence of neutropenia, bacterial infections and systemic complications. These results suggest that different genes and proteins modulate neutrophil differentiation, maturation and apoptosis and thus the severity and frequency of infections. The absence of detectable mutations in three patients could suggest that a second protein plays a role in microsomal phosphate transport.

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by developmental delay and multiple malformations. Some of the patients have skin photosensitivity and therefore tend to avoid direct exposure to sunlight.SLOS patients typically have low concentrations of cholesterol and abnormally high concentrations of its precursor 7-dehydrocholesterol (7-DHC) in biological fluids and tissues. 7-DHC is also a precursor in the cutaneous synthesis of vitamin D. Sunlight exposure plays a major role in this pathway and reactions transforming 7-DHC into vitamin D and then into 25-hydroxyvitamin D are known not to be specifically regulated. The aim of this study was to evaluate vitamin D status in SLOS patients. We measured 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations and markers of calcium metabolism in five SLOS patients. Despite abnormally high concentrations of 7-DHC, circulating concentrations of vitamin D metabolites were not significantly different from appropriate controls matched for sex, age and season of blood collection. The analysis of historical serum samples stored in our laboratory from the same cases plus 10 other SLOS patients further supported these findings. Our data suggest that SLOS patients have a peculiar vitamin D metabolism that protects them from vitamin D intoxication. This appears to be due in most cases to decreased transformation of 7-DHC into 25-hydroxyvitamin D, perhaps depending on reduced sunlight exposure as a consequence of photosensitivity. Possible alternative mechanisms are discussed.

We present a case of recurrent pulmonary alveolar proteinosis after heart-lung transplantation in a child with lysinuric protein intolerance. The recurrence of the pulmonary disease provides further insight regarding the possible pathogenesis of pulmonary alveolar proteinosis and therapeutic options for this complication.

We report on the clinical and molecular characterization of 3 sibs with X-linked ichthyosis and variable expression of Kallmann syndrome. One of the affected brothers had mild hyposmia and showed normal pubertal progression. However, we demonstrated the same partial deletion of the X-linked Kallmann gene, sparing the first exon in the mildly affected patient as well as in one of his severely affected brothers.

Baraitser-Winter syndrome is a rare autosomal recessive disorder characterized by developmental delay, dysmorphic features, and multiple malformations also involving the brain. We report a further case and provide updated information about an unrelated girl reported in the original paper by Baraitser and Winter. Both of them presented with pachygyria and the latter case was recently found to have subcortical band heterotopia on high resolution brain MRI imaging. These two patients and a review of the previously reported cases indicate that a specific pattern of brain anomalies falling in the agyria-pachygyria-band spectrum is associated with this dysmorphic syndrome, which may be considered another example of syndromic neuronal migration defect.

In individuals with non-neuronopathic Gaucher disease, childhood manifestations are usually predictive of a more severe phenotype. Although children with Gaucher disease are at risk of irreversible disease complications, early intervention with an optimal dose of enzyme therapy can prevent the development of complications and ensure adequate, potentially normal, development through childhood and adolescence. Very few, if any, children diagnosed by signs and symptoms should go untreated. Evidence suggests that disease severity, disease progression and treatment response in different organs where glucocerebroside accumulates are often non-uniform in affected individuals. Therefore, serial monitoring of the affected compartments is important. This should include a thorough physical examination at 6- to 12-monthly intervals. Neurological assessment should be performed to rule out neurological involvement and should be undertaken periodically thereafter in children who are considered to have risk factors for developing neuronopathic disease. Haematological and biochemical markers, such as haemoglobin, platelet counts and chitotriosidase levels, should be assessed every 3 months initially, but when clinical goals have been met through treatment with enzyme therapy, the frequency can be reduced to every 12 to 24 months. Careful monitoring of bone disease is vitally important, as the resulting sequelae are associated with the greatest level of morbidity. By combining various imaging modalities, the skeletal complications of non-neuronopathic Gaucher disease can be effectively monitored so that irreversible skeletal pathology is avoided and pain due to bone involvement is diminished or eliminated. Monitoring must include regular psychosocial, functional status and quality-of-life evaluation, as well as consistent assessment of therapeutic goal attainment and necessary dosage adjustments based on the patient's progress. CONCLUSION: Through comprehensive and serial monitoring, ultimately, a therapeutic dose of enzyme therapy that achieves sustained benefits can be found for each child with non-neuronpathic Gaucher disease.

Purpose: To assess whether interactions of common alleles of two folate genes contribute to spina bifida risk. Methods: Case-control study, comparing 203 children with spina bifida to 583 controls. Results: Homozygosity for the 677C-T allele of 5,10-methylenetetrahydrofolate reductase (MTHFR) alone was associated with an odds ratio for spina bifida of 1.57 (95% confidence interval [CI], 1.02–2.38). For the 844ins68 allele of cystathionine-β-synthase alone, the odds ratio was 0.83 (95% CI, 0.39–1.64). For the joint genotype, the odds ratio was 3.69 (95% CI, 1.04–13.50). Conclusions: Interactions between common alleles of folate genes might contribute to the risk for spina bifida.

We report on a girl with a trisomy 1q42-q44 due to an inverted duplication of this region, associated with a terminal deletion of the long arm of the rearranged chromosome 1. Both the large duplication (more than 30 cM) and the small deletion were detected by FISH. Complete karyotype was: (46,XX, inv dup(1)(q44q42).ish(dup del 1)(q44q42)(D1S446x2, D1S423x2, tel1q-). The phenotype of the patient is characterized by macrocephaly with prominent forehead, downslanting palpebral fissures, micrognathia, and psychomotor retardation. All these clinical features are the same as observed for the typical trisomy 1q42-qter syndrome. The phenotypic effects of the inversion and the terminal deletion of 1q in addition to the trisomy are discussed here.

Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive disorder, is characterized by insensitivity to pain, self-mutilating behaviour, anhidrosis and recurrent hyperpyrexia. It is a hereditary sensory and autonomic neuropathy, also classified as HSAN, due to a defect of the receptor for nerve growth factor. CIPA is the first human genetic disorder caused by a defect in the neurotrophin signal transduction system. This is the first clinical report of CIPA patients characterized on molecular grounds. The clinical phenotypes of our patients show that CIPA is characterized by a multisystem involvement besides the nervous system, including bone fracture with slow healing, immunologic abnormalities, such as low response to specific stimuli, chronic inflammatory state ending in systemic amyloidosis. The molecular characterization allows a better understanding of most of the clinical features.

We report on a 21 month old child referred to us because of facial dysmorphism and psychomotor retardation. The patient's phenotype was characterised by a wide and receding forehead, broad nasal bridge, redundant retronuchal skin, low set and poorly shaped ears, micrognathia, and small hands and feet. High resolution R and G banding karyotype analysis of peripheral blood lymphocytes showed an interstitial deletion of the long arm of chromosome 1 spanning bands q22 to q24. The cytogenetic results were confirmed by molecular analysis. The phenotype observed in our patient was relatively milder than those reported in other patients with an interstitial deletion of chromosome 1q.

Objectives To investigate the growth hormone (GH)-insulin-like growth factor (IGF) system in patients with glycogen storage disease type 1 (GSD1). Study design This was a prospective, case-control study. Ten patients with GSD1a and 7 patients with GSD1b who were given dietary treatment and 34 sex-, age-, body mass index-, and pubertal stage-matched control subjects entered the study. Auxological parameters were correlated with circulating GH, either at basal or after growth hormone releasing hormone plus arginine test, insulin-like growth factors (IGF-I and IGF-II), and anti-pituitary antibodies (APA). Results Short stature was detected in 10.0% of patients with GSD1a, 42.9% of patients with GSD1b ( P = .02), and none of the control subjects. Serum IGF-I levels were lower in patients with GSD1b ( P = .0001). An impaired GH secretion was found in 40% of patients with GSD1a ( P = .008), 57.1% of patients with GSD1b ( P = .006), and none of the control subjects. Short stature was demonstrated in 3 of 4 patients with GSD1b and GH deficiency. The prevalence of APA was significantly higher in patients with GSD1b than in patients with GSD1a ( P = .02) and control subjects ( P = .03). The GH response to the provocative test inversely correlated with the presence of APA ( P = .003). Compared with levels in control subjects, serum IGF-II and insulin levels were higher in both groups of patients, in whom IGF-II levels directly correlated with height SD scores ( P = .003). Conclusion Patients with GSD1a have an impaired GH secretion associated with reference range serum IGF-I levels and normal stature, whereas in patients with GSD1b, the impaired GH secretion, probably because of the presence of APA, was associated with reduced IGF-I levels and increased prevalence of short stature. The ncreased IGF-II levels, probably caused by increased insulin levels, in patients with GSD1 are presumably responsible for the improved growth pattern observed in patients receiving strict dietary treatment.

OBJECTIVE: To investigate the hypothalamus-pituitary-thyroid axis in patients with glycogen storage disease type 1(GSD1). STUDY DESIGN: Ten patients with GSD1a, 7 patients with GSD1b, and 34 sex- and age-matched healthy control subjects were enrolled in the study. RESULTS: The levels of serum-free thyroxine (FT4) were significantly lower in patients with GSD1a and GSD1b (P < .05), whereas thyrotropin was significantly higher compared with control subjects only in patients with GSD1b (P < .005). Thyroglobulin and thyroperoxidase auto-antibodies were significantly higher in patients with GSD1b than in patients with GSD1a and control subjects (P < .005). After thyrotropin-releasing hormone stimulation, an enhanced thyrotropin response was found in patients with GSD1a and patients with GSD1b (P < .005) compared with control subjects. The presence of a subclinical or overt hypothyroidism was found in 4 of 7 patients with GSD1b and in no patient with GSD1a (chi2 = 7.47, P < .005) or control subject (chi2 = 27.2, P < .0001). CONCLUSIONS: Patients with GSD1b have an increased prevalence of thyroid autoimmunity and hypothyroidism, although patients with GSD1a have little evidence of thyroid abnormalities. Concomitant damage at the level of the hypothalamus or pituitary gland might be hypothesized on the basis of the slightly elevated thyrotropin levels, even in patients with overt hypothyroidism.

Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive disorder, is characterized by insensitivity to pain, self-mutilating behaviour, anhidrosis and recurrent hyperpyrexia. It is a hereditary sensory and autonomic neuropathy, also classified as HSAN, due to a defect of the receptor for nerve growth factor. CIPA is the first human genetic disorder caused by a defect in the neurotrophin signal transduction system. This is the first clinical report of CIPA patients characterized on molecular grounds. The clinical phenotypes of our patients show that CIPA is characterized by a multisystem involvement besides the nervous system, including bone fracture with slow healing, immunologic abnormalities, such as low response to specific stimuli, chronic inflammatory state ending in systemic amyloidosis. The molecular characterization allows a better understanding of most of the clinical features.

We describe a case of semi-lethal chondrodysplasia with skeletal manifestations, detectable at birth, typical of the round femoral inferior epiphysis dysplasia (RFIED) or 'Glasgow' variant. Immunological abnormalities and Hirschsprung disease, so far described only in cartilage hair hypoplasia (CHH), were documented during the first months of life in our patient. These findings confirm the hypothesis that RFIED is a form of CHH with early infantile onset.

We report on 2 patients with the Neuhäuser megalocornea-mental retardation syndrome, a recessively inherited clinical entity of relatively recent description (McKusick 24931). A review of the few previous reported patients and our 2 patients shows that megalocornea and mental retardation are the 2 minimal diagnostic criteria. Short stature, seizures, neurological symptoms, microcephaly or macrocephaly, and minor anomalies are all additional nonobligatory manifestations. The small number of published cases may be due to the fact that the association of these two signs has often escaped attention until now.

We report the clinical, biochemical, and molecular characterization of a patient with a novel defect of cholesterol biosynthesis. This patient presented with a complex phenotype, including multiple congenital anomalies, mental retardation, and liver disease. In the patient's plasma and cells, we found increased levels of lathosterol. The biosynthesis of cholesterol in the patient's fibroblasts was defective, showing a block in the conversion of lathosterol into 7-dehydrocholesterol. The activity of 3beta-hydroxysteroid-Delta(5)-desaturase (SC5D), the enzyme involved in this reaction, was deficient in the patient's fibroblasts. Sequence analysis of the SC5D gene in the patient's DNA, showing the presence of two missense mutations (R29Q and G211D), confirmed that the patient is affected by a novel defect of cholesterol biosynthesis.

Nineteen homocystinuric patients--13 children and 6 adults--were identified in the course of a selective screening for homocystinuria due to cystathionine synthase deficiency. Treatment with high doses (300-1200 mg/day) of pyridoxine was carried out in 17 patients, of whom 15 were completely responsive. In 10 patients EEG abnormalities were observed consisting mainly of a mild diffuse non specific slowing of background activity. In two sisters, with no history of seizures, focal paroxymal activity was also recorded. EEG recordings before and after B6 treatment were available in 16 patients, one of whom was a non responder, during treatment seven normal and six abnormal EEGs showed no change whereas three previously abnormal EEGs were classified as normal.