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Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thrive. Later in childhood, the brother developed cystinuria and nephrolithiasis whereas the older sister suffered from cystinuria and chronic neurobehavioral disturbances. Biopsied muscle studies demonstrated deficient cytochrome c oxidase activities consistent with a mitochondrial disease. Whole exome sequencing (WES), however, revealed a homozygous 2p21 deletion involving two contiquous genes, SLC3A1 (deletion of exons 2-10) and PREPL (deletion of exons 2-14). The molecular findings were consistent with the hypotonia-cystinuria 2p21 deletion syndrome, presenting similarly in infancy with mitochondrial dysfunction but diverging later in childhood and displaying intrafamilial phenotypic variability., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Significant clinical symptoms of Cohen syndrome (CS), a rare autosomal recessive disorder, include intellectual disability, facial dysmorphism, postnatal microcephaly, retinal dystrophy, and intermittent neutropenia. CS has been associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, which regulates vesicle-mediated protein sorting and transport; however, the cellular mechanism underlying CS pathogenesis in patient-derived neurons remains uncertain. This report states that autophagic vacuoles accumulate in CS fibroblasts and the axonal terminals of CS patient-specific induced pluripotent stem cells (CS iPSC)-derived neurons; additionally, autophagic flux was significantly increased in CS-derived neurons compared to control neurons. VPS13B knockout HeLa cell lines generated using the CRISPR/Cas9 genome editing system showed significant upregulation of autophagic flux, indicating that VSP13B may be associated with autophagy in CS. Transcriptomic analysis focusing on the autophagy pathway revealed that genes associated with autophagosome organization were dysregulated in CS-derived neurons. ATG4C is a mammalian ATG4 paralog and a crucial regulatory component of the autophagosome biogenesis/recycling pathway. ATG4C was significantly upregulated in CS-derived neurons, indicating that autophagy is upregulated in CS neurons. The autophagy pathway in CS neurons may be associated with the pathophysiology exhibited in the neural network of CS patients.

Purpose: The aim of this study is to report on the phenotype and genotype of five patients diagnosed with Cohen syndrome, an extremely rare autosomal recessive disorder manifesting with mental and physiological defects., Methods: Five patients from three German families and one Syrian family underwent a comprehensive ophthalmological examination. The scheduled visual acuity measurements, fundus ophthalmoscopy, spectral domain optical coherence tomography (OCT), full-field electrophysiological recordings of scotopic and photopic electroretinograms (ERGs) and colour vision testing could not be carried out in all subjects, because of the mental and physical retardation. The genetic diagnosis was achieved by next-generation sequencing., Results: The ophthalmic and systemic phenotype of the patients is typical for Cohen syndrome including myopia, night blindness, photophobia, fundus pigmentary changes and bull's eye maculopathy. Electroretinograms (ERGs) were extinguished in the four patients, whose recording was possible. Genetic testing revealed homozygous or two heterozygous bi-allelic mutations in the VPS13B (COH1) gene in all five patients, with five different allelic variants observed. The homozygous mutation c.6055_6056delGA; p.Asp2019Glnfs*15 in two sibling patients as well as the homozygous nonsense mutation c.8112C>G;p.Tyr2704* have not previously been reported., Conclusions: The phenotype of the five patients reported here is typical for Cohen syndrome; however, their genotype is heterogeneous. Two new allelic variants were found to be the causative mutation., (© 2019 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders., (© 2020 Elsevier Inc. All rights reserved.)

De novo pathogenic variants in the human immunodeficiency virus enhancer type I binding protein 2 (HIVEP2) gene, a large transcription factor predominantly expressed in the brain have previously been associated with intellectual disability (ID) and dysmorphic features in nine patients. We describe the phenotype and genotype of two additional patients with novel de novo pathogenic HIVEP2 variants, who have previously unreported features, including hyperphagia and Angelman-like features. Exome sequencing was utilized in the investigation of the patients who had previously incurred a rigorous genetic workup for their neurodevelopmental delay, and in whom no genetic cause had been detected. Information pertaining to phenotype and genotype for new patients was collated along with data from previous reports, showing that the phenotypic spectrum of patients with HIVEP2 variants is broader than first noted. Additional characteristics are: an increased body mass index; and features of Angelman-like syndromes including: ID, limited speech, post-natal microcephaly, and hypotonia. Dysmorphic features vary between patients. As yet, no clear association between the type of gene aberration and phenotype can be concluded. HIVEP2-related ID needs to be considered in the differential diagnosis of patients with Angelman-like phenotypes and hyperphagia, and whole-exome sequencing should be considered in the genetic diagnostic armamentarium for patients with ID of inconclusive etiology., (© 2019 Wiley Periodicals, Inc.)

Objective: To assess the clinical and biochemical features as well as outcome of hyperphenylalaninemia patients., Methods: The descriptive retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data from January 2013 to February 2017 of plasma amino acid analysed at the Biochemical Genetic Laboratory of patients with phenylalanine levels >120 umol/L. Medical charts of patients registered with the Metabolic Clinics were reviewed, while outside referrals were contacted by telephone to collect data on a pre-structured questionnaire. Data was analysed using SPSS 21., Results: Of the 18 patients, 13(72%) were males. Overall median age was 606 days (interquartile range: 761) and median phenylalanine levels were 1280 (interquartile range: 935) umol/L. Phenylalanine hydroxylase deficiency was present in 5(28%) patients while 3(16.6%) had defects in the metabolism or regeneration of tetrahydrobiopterin. The most common clinical features was intellectual deficit and seizures 14(78%) each, followed by lighter hair colour 10(55.5%) and hypotonia 11(61%). High treatment cost was the leading reason for cessation of therapy in 7(39%) followed by refusal by patient's family 5(28%)., Conclusions: Most hyperphenylalaninemia cases were diagnosed late when intellectual disability had already developed.

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor., (© 2018 Wiley Periodicals, Inc.)

Biallelic mutations in NALCN are responsible for infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1). Common features of this condition include severe neonatal-onset hypotonia and profound global developmental delay. Given the rarity of this condition, long-term natural history studies are limited. Here, we present a 9-year-old male with a homozygous nonsense mutation in NALCN (c.3910C>T, p.Arg1304X) leading to profound intellectual disability, seizures, feeding difficulties, and significant periodic breathing. Breathing irregularity was also reported in three previous patients; similar to our patient, those children demonstrated periodic breathing that was characterized by alternating apneic periods with deep, rapid breathing. As the phenotype associated with NALCN mutations continues to be delineated, attention should be given to abnormal respiratory patterns, which may be an important distinguishing feature of this condition.

Hypotonia-cystinuria syndrome is a very rare autosomal recessive contiguous gene deletion syndrome of PREPL and SLC3A1 at 2p21 with neuromuscular and neuroendocrinologic presentation. We report a two-year-six-month-old affected female infant and her five-month-old affected brother with a novel homozygous deletion in SLC3A1 and PREPL gene. Both of siblings had mild facial dysmorphism, hypotonia, feeding problems, failure to thrive, developmental delay. She also had dilated cardiomyopathy which differ from other reported patients. Therefore cardiomyopathy may also be considered one of the features of hypotonia-cystinuria syndrome. With this case report, we present cardiac manifestation of hypotonia-cystinuria syndrome for the first time. Because of two siblings had hyperechogenic bowel in prenatal sonography, it might be a prenatal marker for HCS.

βIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into βIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding. Nerve biopsies from an individual with a loss-of-function variant had reduced nodal Na + channels and no nodal KCNQ2 K + channels. Modeling the disease in mice revealed that although ankyrinR (AnkR) and βI spectrin can cluster Na + channels and partially compensate for the loss of AnkG and βIV spectrin at nodes of Ranvier, AnkR and βI spectrin cannot cluster KCNQ2- and KCNQ3-subunit-containing K + channels. Our findings define a class of spectrinopathies and reveal the molecular pathologies causing nervous-system dysfunction., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing., (© 2017 Wiley Periodicals, Inc.)

High throughput approaches are continuously progressing and have become a major part of clinical diagnostics. Still, the critical process of detailed phenotyping and gathering clinical information has not changed much in the last decades. Forms of next generation phenotyping (NGP) are needed to increase further the value of any kind of genetic approaches, including timely consideration of (molecular) cytogenetics during the diagnostic quest. As NGP we used in this study the facial dysmorphology novel analysis (FDNA) technology to automatically identify facial phenotypes associated with Emanuel (ES) and Pallister-Killian Syndrome (PKS) from 2D facial photos. The comparison between ES or PKS and normal individuals expressed a full separation between the cohorts. Our results show that NPG is able to help in the clinic, and could reduce the time patients spend in diagnostic odyssey. It also helps to differentiate ES or PKS from each other and other patients with small supernumerary marker chromosomes, especially in countries with no access to more sophisticated genetic approaches apart from banding cytogenetics. Inclusion of more facial pictures of patient with sSMC, like isochromosome-18p-, cat-eye-syndrome or others may contribute to higher detection rates in future., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pepper's syndrome is a neuroblastoma that metastasizes to the liver. It affects infants younger than six months of age. It can regress spontaneously and is associated with a favorable prognosis in 80% of cases. Given its rarity, we here report two cases of Pepper's syndrome observed at the Charles de Gaulle university pediatric hospital center, Ouagadougou (Burkina Faso). Our study involved two female infants in whom the disease manifested as an increase in abdominal volume, hepatomegaly and signs of respiratory distress. Ultrasound enabled diagnosis, which was based on the nodular appearance of the liver in both cases and determination of the primary tumor in one case. Urinary catecholamine test confirmed the diagnosis in one case. Both patients died from complications related to liver compression, chemotherapy (in one of the cases) and lack of treatment (in the other case).

DOCK3 encodes the dedicator of cytokinesis 3 protein, a member of the DOCK180 family of proteins that are characterized by guanine-nucleotide exchange factor activity. DOCK3 is expressed exclusively in the central nervous system and plays an important role in axonal outgrowth and cytoskeleton reorganization. Dock3 knockout mice exhibit motor deficiencies with abnormal ataxic gait and impaired learning. We report 2 siblings with biallelic loss-of-function variants in DOCK3. Diagnostic whole-exome sequencing (WES) and chromosomal microarray were performed on a proband with severe developmental disability, hypotonia, and ataxic gait. Testing was also performed on the proband's similarly affected brother. A paternally inherited 458 kb deletion in chromosomal region 3p21.2 disrupting the DOCK3 gene was identified in both affected siblings. WES identified a nonsense variant c.382C>G (p.Gln128*) in the DOCK3 gene (NM_004947) on the maternal allele in both siblings. Common features in both affected individuals include severe developmental disability, ataxic gait, and severe hypotonia, which recapitulates the Dock3 knockout mouse phenotype. We show that complete DOCK3 deficiency in humans leads to developmental disability with significant hypotonia and gait ataxia, probably due to abnormal axonal development., (© 2017 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in VPS13B, also known as COH1. Over 100 pathogenic variants in VSP13B, primarily truncations, and copy number variants, have been found in patients with CS. Here, we present an 11-month-old girl with CS caused by two multi-exonic small deletions in VSP13B in trans. Array comparative genomic hybridization has revolutionized the field of genome copy number analysis down to the exonic level, however it has its limitations. It cannot detect balanced structural variation nor determine the phase of copy number variants. Heterozygous multi-exonic copy number variation in autosomal recessive genes should be interpreted in the context of a clinical phenotype, and, if warranted, phase analysis should be performed before sequence analysis for that gene is pursued. This patient emphasizes the need of obtaining clinical information and determining the phase in multi-exonic copy number variants for accurate diagnosis and risk counseling., (© 2017 Wiley Periodicals, Inc.)

MED12 is a multiprotein mediator complex, which has a role in cell growth and differentiation and has been implicated in three distinct X-linked intellectual disability syndromes with distinctive clinical features. These include Opitz-Kaveggia syndrome (FG syndrome), Lujan syndrome, and X-linked Ohdo syndrome. Recently MED12 variants have been implicated in isolated X-linked intellectual disability. We describe a 5-year-old male patient with intellectual disability and facial dysmorphism and a novel variant in MED12 gene identified by Whole Exome Sequencing. His dysmorphic facial features are distinct from the previously described phenotypes. With a strong genotype-phenotype correlation that is already known for MED12, this could be a new phenotype linked to MED12, thus expanding the phenotypic spectrum of MED12-related disorders., (© 2017 Wiley Periodicals, Inc.)

We evaluated a 13-year-old East Pakistani male affected with microcephaly, apparent intellectual disability, hypotonia, and brisk reflexes without spasticity. His parents were first cousins. The patient also had a brother who was similarly affected and died at 10 years due to an accident. Previous SNP array testing showed a 1.63 Mb duplication at 16p13.11 of uncertain significance along with regions of homozygosity. Exome sequencing identified a known pathogenic homozygous alteration in DEAF1, c.676C>T (p.R226W), in this patient. The alteration had been reported in two individuals from a consanguineous Saudi Arabian family. Both individuals had microcephaly, intellectual disability, hypotonia, feeding difficulties, and poor growth. The patient reported here did not have evidence of white matter disease, as had been reported with prior patients. We conclude that this DEAF1 gene alteration caused this patient's symptoms and that white matter disease should not be considered a obligate feature of this syndrome., (© 2016 Wiley Periodicals, Inc.)

Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective glycosylation secondary to mutations in the VPS13B gene, which encodes a protein of the Golgi apparatus. Besides congenital neutropenia, retinopathy and intellectual deficiency, CS patients are faced with truncal obesity. Metabolism investigations showed abnormal glucose tolerance tests and low HDL values in some patients, and these could be risk factors for the development of diabetes mellitus and/or cardiovascular complications. To understand the mechanisms involved in CS fat storage, we used two models of adipogenesis differentiation: (i) SGBS pre-adipocytes with VPS13B invalidation thanks to siRNA delivery and (ii) CS primary fibroblasts. In both models, VPS13B invalidation led to accelerated differentiation into fat cells, which was confirmed by the earlier and increased expression of specific adipogenic genes, consequent to the increased response of cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 phosphorylation after insulin stimulation, which suggests insulin resistance. This study, in association with the in-depth analysis of the metabolic status of the patients, thus allowed us to recommend appropriate nutritional education to prevent the occurrence of diabetes mellitus and to put forward recommendations for the follow-up of CS patients, in particular with regard to the development of metabolic syndrome. We also suggest replacing the term obesity by abnormal fat distribution in CS, which should reduce the number of inappropriate diagnoses in patients who are referred only on the basis of intellectual deficiency associated with obesity., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

FG syndrome, Lujan syndrome, and Ohdo syndrome, the Maat-Kievit-Brunner type, have been described as distinct syndromes with overlapping non-specific features and different missense mutations of the MED12 gene have been reported in all of them. We report a family including 10 males and 1 female affected with profound non-specific intellectual disability (ID) which was linked to a 30-cM region extending from Xp11.21 (ALAS2) to Xq22.3 (COL4A5). Parallel sequencing of all X-chromosome exons identified a frameshift mutation (c.5898dupC) of MED12. Mutated mRNA was not affected by non-sense mediated RNA decay and induced an additional abnormal isoform due to activation of cryptic splice-sites in exon 41. Dysmorphic features common to most affected males were long narrow face, high forehead, flat malar area, high nasal bridge, and short philtrum. Language was absent or very limited. Most patients had a friendly personality. Cognitive impairment, varying from borderline to profound ID was similarly observed in seven heterozygous females. There was no correlation between cognitive function and X-chromosome inactivation profiles in blood cells. The severe degree of ID in male patients, as well as variable cognitive impairment in heterozygous females suggests that the duplication observed in the present family may have a more severe effect on MED12 function than missense mutations. In a cognitively impaired male from this family, who also presented with tall stature and dysmorphism and did not have the MED12 mutation, a 600-kb duplication at 17p13.3 including the YWHAE gene, was found in a mosaic state., (© 2013 Wiley Periodicals, Inc.)

Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is generally raised after school age, when visual disturbances lead to CRD diagnosis and to VPS13B gene testing. This relatively late diagnosis precludes accurate genetic counselling. The aim of this study was to analyse the evolution of CS facial features in the early period of life, particularly before school age (6 years), to find clues for an earlier diagnosis. Photographs of 17 patients with molecularly confirmed CS were analysed, from birth to preschool age. By comparing their facial phenotype when growing, we show that there are no special facial characteristics before 1 year. However, between 2 and 6 years, CS children already share common facial features such as a short neck, a square face with micrognathia and full cheeks, a hypotonic facial appearance, epicanthic folds, long ears with an everted upper part of the auricle and/or a prominent lobe, a relatively short philtrum, a small and open mouth with downturned corners, a thick lower lip and abnormal eye shapes. These early transient facial features evolve to typical CS facial features with aging. These observations emphasize the importance of ophthalmological tests and neutrophil count in children in preschool age presenting with developmental delay, hypotonia and the facial features we described here, for an earlier CS diagnosis.

Background: Trapped Neutrophil Syndrome (TNS) is a common autosomal recessive neutropenia in Border collie dogs., Results: We used a candidate gene approach and linkage analysis to show that the causative gene for TNS is VPS13B. We chose VPS13B as a candidate because of similarities in clinical signs between TNS and Cohen syndrome, in human, such as neutropenia and a typical facial dysmorphism. Linkage analysis using microsatellites close to VPS13B showed positive linkage of the region to TNS. We sequenced each of the 63 exons of VPS13B in affected and control dogs and found that the causative mutation in Border collies is a 4 bp deletion in exon 19 of the largest transcript that results in premature truncation of the protein. Cohen syndrome patients present with mental retardation in 99% of cases, but learning disabilities featured in less than half of TNS affected dogs. It has been implied that loss of the alternate transcript of VPS13B in the human brain utilising an alternate exon, 28, may cause mental retardation. Mice cannot be used to test this hypothesis as they do not express the alternate exon. We show that dogs do express alternate transcripts in the brain utilising an alternate exon homologous to human exon 28., Conclusion: Dogs can be used as a model organism to explore the function of the alternately spliced transcript of VPS13B in the brain. TNS in Border collies is the first animal model for Cohen syndrome and can be used to study the disease aetiology.

3-M syndrome is an autosomal recessive primordial growth disorder characterised by severe postnatal growth restriction caused by mutations in CUL7, OBSL1 or CCDC8. Clinical characteristics include dysmorphic facial features and fleshy prominent heels with a variable degree of radiological abnormalities. CUL7 is a structural protein central to the formation of an ubiquitin E3 ligase that is known to target insulin receptor substrate 1 for degradation. CUL7 also binds to p53 and may be involved in the control of p53-dependent apoptosis. OBSL1 is a cytoskeletal adaptor protein that was thought to play a central role in myocyte remodelling, and CCDC8 has no defined function as yet. However, the physical interaction of OBSL1 with both CUL7 and CCDC8 and its potential role in the regulation of CUL7 expression suggest all three proteins are members of the same growth-regulatory pathway. Future work should be directed to investigating the function of the 3-M syndrome pathway and in particular the role in the insulin like growth factor I signalling pathway with a view of potentially revealing new therapeutic targets and identifying key regulators of cellular growth., (Copyright © 2011 S. Karger AG, Basel.)

Opitz and Kaveggia [Opitz and Kaveggia (1974); Z Kinderheilkd 117:1-18] reported on a family of five affected males with distinctive facial appearance, mental retardation, macrocephaly, imperforate anus, and hypotonia. Risheg et al. [Risheg et al. (2007); Nature Genetics 39:451-453] identified an identical mutation (p.R961W) in MED12 in six families with Opitz-Kaveggia syndrome, including a surviving affected man from the original family reported in 1974. The previously described behavior phenotype of hyperactivity, affability, and excessive talkativeness is very frequent in young boys with FG syndrome, along with socially oriented, attention-seeking behaviors. We present case studies of five adult males who were previously published with the clinical diagnosis of FG syndrome and then subsequently proven by Risheg et al. [Risheg et al. (2007); Nature Genetics 39:451-453] to have the recurrent p.R961W mutation. These individuals had episodic and longstanding behavior patterns, sometimes aggressive or self-abusing, that occurred more frequently in puberty and early adulthood. We try to describe the triggers for these behaviors, indicate how these behaviors change with advancing age, and suggest specific recommendations and interventional strategies based on the clinical histories of affected adolescent males with FG syndrome [Graham et al., 2008; Clark et al., 2009]. Young men who exhibit these behaviors may benefit from a careful examination to detect medical problems, use of mood stabilizers if needed, and/or behavioral intervention. The transition to a community living situation can be challenging without careful planning and timely behavioral intervention. They remain impulsive and can have aggressive outbursts when making the transition to adult life, but these challenges can be managed, as demonstrated by these clinical histories., (© 2010 Wiley-Liss, Inc.)

The purpose of this study was to assess the respiratory muscle strength (RMS) in individuals with mental retardation (MR), with or without Down Syndrome (DS), and its association with bone mineral density (BMD). Forty-five male individuals (15 with DS, 15 with mental retardation (MR) and 15 apparently healthy controls), aged 20-35, participated in this study. Subject assessment included pulmonary function tests, RMS (maximal inspiratory pressure, MIP, and maximal expiratory pressure, MEP) and BMD of the second and fourth lumbar vertebrae. ANOVA was used to test differences amongst groups. Tukey post hoc test was utilized when significant differences were detected with ANOVA. Bivariate correlation for BMD and respiratory muscle strength was calculated with Pearson's coefficient of correlation. Individuals with MR, both with and without DS, have lower FEV1, FVC, MIP and MEP (p<0.001) compared to controls. Individuals with DS also had lower BMD, which was associated with lower MIP and MEP. Hypotonia, sedentary lifestyle and obesity are factors that may explain lower MIP and MEP in DS. Strategies to increase RMS could decrease the risk of osteoporosis in the DS population., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

We present hypothesized ocular motor mechanisms of unique "staircase-like" sequences of saccadic intrusions in one direction that we have named, "staircase saccadic intrusions (SSI)," square-wave jerks/oscillations (SWJ/SWO), and transient failures of yoking and neural integrators in a patient with severe hypotonia, ataxic speech, motor and language developmental delays, and torticollis (Joubert syndrome). Brain magnetic resonance imaging showed hypoplasia of the cerebellar vermis and inferior cerebellar peduncles, abnormal superior cerebellar peduncles with deepening of the interpeduncular fossa, and enlargement of the fourth ventricle. During far and near fixation and smooth pursuit (rightward markedly better than leftward), the subject exhibited conjugate SSI (rightward more than leftward, with intersaccadic intervals equivalent to the normal 250 msec visual latency), SWJ, SWO, and uniocular, convergent and divergent saccades (including double saccades). Simulations using a behavioral ocular motor system model identified hypothetical mechanisms for SWJ, SWO, and SSI and ruled out the loss of efference copy as the cause. SSI may result from simultaneous dysfunctions: 1) a transient loss of accurate retinal-error information and/or sampled, reconstructed error; plus 2) a constant sampled, reconstructed retinal error that drives saccades.

Cohen syndrome is a rare, genetic, connective-tissue disorder with the genetic abnormality linked to chromosome 8q22. The diagnosis of Cohen syndrome is based on the recognition of certain clinical findings, which include mental retardation, typical morphologic stigmata (e.g., truncal obesity, hypotonia, short philtrum, prominent frontal incisors, high-arched palate, narrow hands and feet), and characteristic ophthalmologic abnormalities. We report a patient manifesting the typical characteristics of Cohen syndrome with seizure and hyperinsulinemia.

Purpose: To analyze the mechanisms of myopia in Cohen syndrome (Mendelian Inheritance in Man [MIM] no. 216550)., Methods: A cross-sectional study of 22 Finnish patients (age range, 2-57 years) with Cohen syndrome, which maps to chromosome 8q22, was undertaken to record cycloplegic refraction, keratometry (corneal power and radius of curvature), biometry (anterior chamber depth [ACD], lens thickness [LT], axial [AL] and vitreal length [VL]), and Hoffer Q-modeled lens power. These components of refraction were correlated to age and spherical equivalent (SE) at the corneal plane. Contribution to total myopia of refractive (corneal and lenticular) and axial components was modeled by multiple linear regression and by estimating the effect of deviation from population mean values., Results: The mean SE in patients with Cohen syndrome older than 10 years was -9.35 D; the mean cylinder power, +1.70 D; and the mean anisometropia, 0.53 D. Relative to the emmetropic eye of a young adult, the AL and VL (mean, 23.9 and 16.6 mm, respectively) and lens power (mean, 30.30 D) were higher in 74% and 93% of patients, respectively, and the ACD (mean, 2.5 mm) was smaller and the LT (mean, 4.9 mm) and corneal power (mean, 45.63 D) higher than average in all patients. Corneal power (r = 0.513, P = 0.021) increased with age, but AL and VL (P = 0.46 and 0.54, respectively) and lens power (P = 0.89) did not correlate with age. The lens power decreased with AL (r = -0.564, P = 0.029) and tended to increase with corneal power (r = 0.475, P = 0.074). Multiple linear regression identified AL and corneal power as independent predictors of SE. Based on deviation from population means, the lens power explained 55%, corneal power 23%, and AL 22% of total myopia. ACD decreased and LT increased markedly with age, rendering angle-closure glaucoma a possibility., Conclusions: Myopia in Cohen syndrome is mainly refractive in type and is due to high corneal and lenticular power, which is otherwise rare in young patients. It may be superimposed on axial myopia, probably related to polygenic factors that determine myopia in the general population. The refractive myopia in Cohen syndrome may result from dysgenesis and atrophy of the cornea, ciliary body, and iris, which in turn cause iridial and zonular laxity and spherophakia.

We report four children with unusual facial features including severe blepharophimosis, ptosis, and a distinctive nose with a broad flat tip and a depressed bridge. All four patients were markedly hypotonic and had severe feeding difficulties and developmental delay. Two had congenital heart defects and all three who survived had hypoplastic teeth. Both of the male patients had cryptorchidism. These four children have a distinctive syndrome which is similar to that reported by Biesecker (J Med Genet (1991) 28: 131-134).

Two young siblings with hereditary spastic diplegia and mental retardation (Böök's syndrome) have had detailed clinical investigations since infancy. The inheritance pattern of this syndrome in the present family fits well with an autosomal recessive trait--with affected sibs of opposite sex, born to consanguineous healthy parents.

The aim of this study was to describe the EEGs, brainstem auditory evoked potentials and somatosensory evoked potentials obtained in eleven children with the Zellweger syndrome. In six out of the eleven patients BAEPs and in five of them SSEPs were performed. Severe abnormalities could be demonstrated, reflecting diffuse cerebral dysfunction as well as long myelinated fiber tracts dysfunction. In four of six patients no response was obtained by BAEPs and in two the central conduction time was delayed. The specific (until 60 ms) and aspecific (after 60 ms) complex of the SSEPs was delayed or the potential could not be elicited. During sleep as well as wakefulness characteristic abnormalities of the EEGs were found in nine patients. These abnormalities consisted of continuous negative sharp waves and spikes at the vertex.

Forty girls with Rett syndrome were included in a study of behaviour, with particular regard to the hands, before, during and after regression. Data was taken from examination of each girl, and in some cases from detailed developmental histories given by parents, and films taken before, during and after regression. The important findings are shown in two tables and described. Pre-regression abnormalities included hypotonia, jerky incoordination, an excess of patting or waving activity and involuntary movements which included alternate opening and closing of the fingers and twisting of wrists or arms. Hand use did not progress beyond the ten- to twelve-month stage. Language did not develop beyond the stage of one word utterances. When well-developed, the stereotyped hand movements were simple and clumsy, consisting of tapping, rubbing and clasping, with the hand moved as a unit. Before regression hands were usually separate, during regression usually together and thereafter with increasing age inclined to separate again. Voluntary hand use was observed when girls were relaxed and strongly motivated, particularly during musical interactions. The characteristic abnormalities of behaviour in pre-regression Rett syndrome, and hand behaviour in later childhood should allow earlier and more accurate diagnosis.

A clinical, neurological and electroencephalographic investigation was undertaken in 29 previously cytogenetically verified hemizygous males with the fra(X) form of mental retardation (age range 3.5 to 59 years); in addition, 6 heterozygous females were examined. All male patients displayed the known physical aspects of this syndrome together with associated abnormalities of the palate, skeleton, connective tissue and endocrine system. The most prominent neurological features were different forms of oculomotor disturbances, minor motor and pyramidal signs, incoordination, muscle hypotonia, gait and speech abnormalities. There was no increased frequency either in seizures or in epileptic EEG discharges. Some patients had a slowing of background activity in EEG. About 50% of all patients displayed autistic-like behaviour, short attention span and/or hyperactivity. In accordance with the literature, the findings indicate that there are no neurological, electroencephalographic or neuroradiological features which occur specifically in this syndrome. The need to differentiate the findings from those resulting from encephalopathic mechanisms during the gestational and perinatal period is stressed. A distinct typing of seizures and EEG changes is needed in each patient, before definite conclusions about an association of seizures and fra(X) syndrome are drawn. In view of the lack of correlation between IQ and the clinical-neurological measures, a more practical approach to quantifying the mental impairment is proposed.