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Adenosine kinase (ADK) deficiency is a rare autosomal recessive inborn error of metabolism involving the methionine and purine metabolic pathways. Prior reports show that most patients present in infancy with jaundice, hypotonia, developmental delay, and mild dysmorphic features. Characteristic biochemical findings included hypoglycemic hyperinsulinism, cholestasis, elevated liver functions, methionine, S‐adenosylhomocysteine, and S‐adenosylmethionine, with normal or mildly elevated homocysteine level. Brain imaging demonstrated atrophy, hydrocephalus, and delayed myelination. There are 26 reported patients of ADK deficiency, of which 14 patients were placed on a methionine‐restricted diet. Clinical improvement with methionine restriction was not well described. Case report We report an infant who presented at birth with persistently elevated ammonia (100‐163 μmol/L), hypoglycemia, cholestasis, and liver dysfunction. The initial metabolic and genetic work‐up was nondiagnostic, with only a mildly increased plasma methionine level (51 [

Many patients with inborn errors of metabolism, due to early diagnosis and improved management, are living longer with less disease burden. Several are now having families of their own. This poses challenges both for the metabolic control of the mother and potential secondary effects on the fetus, as well as the risk of inheriting the inborn error. Classical homocystinuria (HCU, OMIM 236200) is a rare multisystem condition with intellectual, skeletal, ocular, and thromboembolic complications. Ireland has included HCU in the National Newborn Bloodspot Screening Program since 1971. The European network and registry for homocystinurias and methylation defects (E‐HOD) guidelines outline the requirements for management and monitoring of this condition and associated complications. Pregnancy alone has many potential complications. When combined with an underlying condition such as HCU, which is prothrombotic and requires a highly medicalized diet, there are significantly increased risks to both mother and baby. Colleagues previously published an Irish case of maternal HCU with successful pregnancy outcome. We add five pregnancies to two women with classical HCU to the literature. We use these to highlight the importance of careful metabolic control and managing the predictable HCU associated risks during pregnancy and the postpartum period. Our cases demonstrate the potential for healthy pregnancies in HCU and that this is best achieved with a motivated clinical team and good patient engagement. Only small numbers of pregnancies in HCU have been reported and we are still learning best practice, but proactive management is essential, as in any inborn error of metabolism.

We report on a 5‐year‐old female born to consanguineous parents, ascertained at the age of 23 months for an elevated plasma methionine level, a mildly abnormal total plasma homocysteine (tHcy), and elevated aminotransferases. She had global developmental delay, microcephaly, dysmorphic facial features, hypotonia, nystagmus and tremor in her upper extremities. Metabolic investigations demonstrated elevations in plasma methionine, plasma S‐adenosylmethionine (SAM) and plasma S‐adenosylhomocysteine (SAH), with normal urine adenosine levels. Some of the elevations persisted for over 1 year. Sequencing of the ADK and AHCY genes was negative for causative variants. Plasma methionine normalized 1 year after ascertainment, but SAM and SAH continued to be elevated for six more months before normalization, and aminotransferases remained mildly elevated. Whole exome sequencing demonstrated a homozygous pathogenic variant; {"type":"entrez-nucleotide","attrs":{"text":"NM_018297.3","term_id":"223941793","term_text":"NM_018297.3"}}NM_018297.3(NGLY1):c.1405C>T (p.Arg469*) in exon 9 of the NGLY1 gene, for which both parents were heterozygous. To our knowledge, this is the first report of NGLY1 deficiency with elevations in plasma methionine, SAM and SAH and a slight elevation of tHcy. Less than 20 patients have been reported with NGLY1 deficiency worldwide and this case expands on the biochemical phenotype of this newly discovered inborn error of metabolism.

Hyperornithinemia‐hyperammonemia‐homocitrullinuria (HHH) syndrome is a rare metabolic autosomal recessive urea cycle disorder. Only about 100 patients have been reported in the literature. As the population survives into reproductive years, pregnancy management becomes a new challenge for this clinicians. To our knowledge, there are less than three patients with successful pregnancies and deliveries found in the literature with no specific consensus on management or recommendations for HHH syndrome. We reviewed the current literature regarding pregnancy outcomes, combine it with our experience managing a patient through two successful pregnancies and identify a new concern of fetal intrauterine growth restriction. From this, recommendations for pregnancy management are made, including a detailed protocol for clinicians to use for disease management at delivery and in the post‐partum period.

Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme in the sialic acid synthesis pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). To date, eight cases had been published worldwide, all with heterozygous missense variants at the allosteric site, specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE. The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice. The apparent rarity of this disorder is hypothesized to be due to the variable and sometimes transient nature of the clinical features and to the absence of routine testing for urinary sialic acids. Here we present the ninth case of sialuria diagnosed in a child investigated because of clinical signs and symptoms and furthermore describe a novel pathogenic variant in the associated gene, GNE.

Fabry disease, a lysosomal storage disorder, is a rare inborn error of metabolism caused by deficiency of the enzyme alpha galactosidase A and resulting accumulation of globotriaosylceramide. The symptoms of Fabry disease are heterogeneous including renal failure, cardiac hypertrophy, and stroke and may not be well recognized by non-specialist physicians. Patients with milder, later onset of disease often have a delay in diagnosis.Fabry patients may suffer significant neuropathic pain in the extremities (acroparasthesia) but the degree to which musculoskeletal symptoms contribute to total pain and disability is unknown. Here, we present a questionnaire study focusing on joint manifestations and their impact on daily life of patients with Fabry disease.Seventy-seven patients with Fabry disease and age-matched healthy controls (49 female and 28 male) took part in a survey focused on joint problems, pain, disability, and quality of life. Joint pain and swelling were reported by 43% of male and 39% of female Fabry patients. Analysis by age group showed higher prevalence of joint problems and decreased quality of life, in terms of mobility, activity, pain, and anxiety, in Fabry patients younger than 50 years compared to healthy controls. Female Fabry patients had higher fatigue scores compared to control subjects. Fabry patients reported problems with vigorous daily activities and gripping.Musculoskeletal symptoms are common in Fabry patients and contribute to overall pain and decreased quality of life. Awareness of Fabry disease by physicians may be raised to ensure timely diagnosis of this rare disease.

Cerebrotendinous xanthomatosis (CTX) is an inborn error of metabolism leading to progressive multisystem disease. Symptoms often begin in the first decade of life with chronic diarrhea, cataracts, developmental delay, intellectual disability, and cerebellar or pyramidal dysfunction. Later manifestations include tendon xanthomas, polyneuropathy, and abnormal neuroimaging. Pathogenic biallelic variants in CYP27A1 leading to compromised function of sterol 27-hydroxylase result in accumulation of detectable toxic intermediates of bile acid synthesis rendering both genetic and biochemical testing effective diagnostic tools. Effective treatment with chenodeoxycholic acid is available, making early diagnosis critical for patient care. Here we report a new patient with CTX and describe the early signs of disease in this patient. Initial symptoms included infantile spasms, which have not previously been reported in CTX. Developmental delay, mild intellectual disability with measured cognitive decline in childhood, was also observed. These clinical signs do not traditionally compel testing for CTX, and we highlight the need to consider this rare but treatable disorder among the differential diagnosis of children with similar clinical presentation. Increased awareness of early signs of CTX is important for improving time to diagnosis for this patient population.

The incidence of succinic semialdehyde dehydrogenase (SSADH) deficiency, an autosomal recessive inherited disorder of GABA degradation, is unknown. Upon a recent diagnosis of a new family of affected fraternal twins from the Punjabi ethnic group of India, case ascertainment from the literature and our database was done to determine the number of confirmed cases along with their geographic distribution. The probands presented with global developmental delay, infantile onset epilepsy, and a persistent neurodevelopmental disorder upon diagnosis at 10 years of age with intellectual disability, expressive aphasia, and behavioral problems most prominent for hyperactivity. Gamma-hydroxybutyric aciduria and homozygous ALDH5A1 c.608C>T; p.Pro203Leu mutations were confirmed. Identification of all available individual cases with clinical details available including geographic or ethnic origin revealed 182 patients from 40 countries, with the largest number of patients reported from the USA (24%), Turkey (10%), China (7%), Saudi Arabia (6%), and Germany (5%). This study provides an accounting of all published cases of confirmed SSADH deficiency and provides data useful in planning further studies of this rare inborn error of metabolism.

Multiple sulfatase deficiency (MSD) is a rare autosomal recessive inborn error of metabolism due to reduced catalytic activity of the different sulfatase. Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and skin changes as in X-linked ichthyosis. The only organ that was not examined in MSD patients is the dentition.To evaluate the effect of the metabolic error on dental development in a patient with the intermediate severe late-infantile form of MSD (S155P).Histological and chemical study were performed on three deciduous and five permanent teeth from MSD patient and pair-matched normal patients.Tooth germ size and enamel thickness were reduced in both deciduous and permanent MSD teeth, and the scalloping feature of the DEJ was missing in MSD teeth causing enamel to break off from the dentin. The mineral components in the enamel and dentin were different.The metabolic error insults the teeth in the stage of organogenesis in both the deciduous and permanent dentition. The end result is teeth with very sharp cusp tips, thin hypomineralized enamel, and exposed dentin due to the break off of enamel. These findings are different from all other types of MPS syndromes.Clinically the phenotype of intermediate severe late-infantile form of MSD appeared during the third year of life. In children of parents that are carriers, we can diagnose the disease as early as birth using X-ray radiograph of the anterior upper region or as early as 6-8 months when the first deciduous tooth erupt and consider very early treatment to ameliorate the symptoms.

Deficiency of pyridox(am)ine 5′-phosphate oxidase (PNPO, OMIM 610090) is a treatable autosomal recessive inborn error of metabolism. Neonatal epileptic encephalopathy and a low cerebrospinal fluid (CSF) pyridoxal 5′-phosphate level are the reported hallmarks of PNPO deficiency, but its clinical and biochemical spectra are not fully known. Case presentation: A girl born at 33 3/7 weeks of gestation developed seizures in the first hours of life. Her seizures initially responded to GABAergic agonists, but she subsequently developed a severe epileptic encephalopathy. Brain MRI and infectious and metabolic evaluations at birth, including urinary alpha-aminoadipic semialdehyde (AASA), were normal. Lumbar puncture at age 3 months showed: pyridoxal 5′-phosphate, 52 nmol/L (normal, 23–64); homovanillic acid, 392 nmol/L (normal, 450–1,132); 5-hydroxyindoleacetic acid, 341 nmol/L (normal, 179–711); and 3-ortho-methyldopa, 30 nmol/L (normal, below 300). The patient was not being treated with pyridoxine nor with pyridoxal 5′-phosphate at the time of the lumbar puncture. She died at age 14 months. A sequencing panel targeting 53 epilepsy-related genes revealed a homozygous missense mutation in PNPO (c.674G>A, p.R225H). Homozygosity was confirmed by parental testing. Expression studies of mutant p.R225H PNPO revealed greatly reduced activity. In conclusion, a normal CSF level of pyridoxal 5′-phosphate does not rule out PNPO deficiency.

Classical galactosemia is an autosomal recessive inborn error of metabolism caused by a deficiency of the galactose-1-phosphate uridyltransferase (GALT). More than 200 mutations have been described in the GALT gene. A 5.5-kb GALT deletion, first described in patients of Ashkenazi Jewish ancestry, may lead either to an erroneous genotype assignment of classical galactosemia or to discrepancies with parental genotypes and the expected biochemical phenotype. The presence of the 5.5-kb deletion was examined in 27 Mexican nonrelated families with at least one child with reduced GALT activity in erythrocytes and it was detected in the 5.5% (n=3) of the 54 alleles tested. The first molecular studies in three of our families showed that the genotypes of the parents were inconsistent with those of their children, which were considered initially as homozygous p.N314D-Duarte 2, but after analyzing for the presence of the 5.5-kb deletion, were reassigned as compound heterozygotes [5.5-kb deletion]+[p.N314D-Duarte 2]. Identification of the 5.5-kb deletion in Mexican patients suggests that this mutation might not be exclusive to a given ethnic group and should be tested in other populations, especially when there is a discrepancy between the genotypes of patients and parents or by incongruence between biochemical phenotype and GALT genotype. Establishing a genotype–phenotype correlation for the 5.5-kb GALT deletion and determining the appropriate management will require additional studies in patients with a G/G genotype bearing the 5.5-kb GALT deletion.