Aysegul Tokatli

Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.

Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of l-lysine, l-hydroxylysine, and l-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n = 218) or presymptomatically by neonatal screening (n = 23), high-risk screening (n = 24), or macrocephaly (n = 14). Most symptomatic patients (n = 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with l-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.

Novel mutations cause biotinidase deficiency in Turkish children

Mutation analysis was performed on DNA from 31 Turkish children with profound biotinidase deficiency who were symptomatic or ascertained by newborn screening. The 98G:del7ins3 mutation is common in clinically ascertained children in both the United States and Turkish populations, but a unique common mutation, R79C, is found only in the Turkish children identified both clinically and by newborn screening. Another frequently occurring mutation, T532M, is only observed in the Turkish newborn screening group. There are four other less frequent novel mutations identified in the Turkish population. Interestingly, the Q456H and the A171T:D444H double mutation, which are the most common mutations found in the US newborn screening population and have not been observed in symptomatic children, do occur in clinically ascertained children in the Turkish population, although the double mutation may be associated with milder and/or later-onset symptoms.

Secondary Hemophagocytosis in 3 Patients With Organic Acidemia Involving Propionate Metabolism

Hemophagocytic lymphohistiocytosis (HLH) may develop secondary to infections, malignancies, immune deficiency syndromes, and rheumatologic and metabolic disorders. Associations between HLH and inborn errors of metabolism, including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, have previously been reported in the literature. In this report the authors present 3 children with disorders of propionate metabolism—1 with methylmalonic acidemia and 2 with propionic acidemia—who developed secondary HLH during their metabolic attacks. All patients fulfilled the 5 HLH criteria of the Histiocyte Society. Familial HLH was ruled out by molecular analysis. Plasma exchange was performed for 2 of them. Unfortunately 1 died of multiorgan failure despite intensive therapy. This is the first report of such an association.

Multisystem fatal infantile disease caused by a novel homozygous EARS2 mutation

Sir, we read with great interest the report describing 12 patients presented with early onset severe neurological disease, characterized by unique MRI features of leukoencephalopathy involving the thalamus and brainstem with high lactate (LTBL; Steenweg et al., 2012). Clinically, the patients fell into two distinct groups. Four patients showed a severe progressive psychomotor regression soon after birth followed by complex irreversible neurological features, however, all patients were alive up to 7 years of age. Eight patients had mild spasticity, seizures and irritability between 6 and 12 months of life with improvement of both clinical and MRI signs in the second year. Stereotypical brain MRI appearances led to molecular diagnosis of mutations in the mitochondrial glutamyl-tRNA synthetase ( EARS2 ) gene. An increasing number of mutations have been identified recently in genes involved in mitochondrial protein synthesis (Smits et al., 2010; Chrzanowska-Lightowlers et al., 2011; Rotig, 2011). Most of these gene defects result in histological [cytochrome c oxidase (COX) deficient or ragged red fibres] and biochemical (multiple respiratory chain defect) abnormalities in affected organs. The clinical phenotypes are usually early-onset, severe, and often fatal diseases, implying the importance of mitochondrial translation from birth. Although some have distinguishing features (Chrzanowska-Lightowlers et al., 2011; Rotig, 2011), as a group they form an overlapping spectrum of disease. The MRI features described by Steenweg et al. (2012) in patients with EARS2 mutations add characteristic radiological features to …

Key features and clinical variability of COG6-CDG.

The conserved oligomeric Golgi (COG) complex consists of eight subunits and plays a crucial role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been detected in patients with congenital disorders of glycosylation (CDG) of variable severity. So far, 3 families with a total of 10 individuals with biallelic COG6 mutations have been described, showing a broad clinical spectrum. Here we present 7 additional patients with 4 novel COG6 mutations. In spite of clinical variability, we delineate the core features of COG6-CDG i.e. liver involvement (9/10), microcephaly (8/10), developmental disability (8/10), recurrent infections (7/10), early lethality (6/10), and hypohidrosis predisposing for hyperthermia (6/10) and hyperkeratosis (4/10) as ectodermal signs. Regarding all COG6-related disorders a genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal CDG phenotypes. A comparison with other COG deficiencies suggests ectodermal changes to be a hallmark of COG6-related disorders. Our findings aid clinical differentiation of this complex group of disorders and imply subtle functional differences between the COG complex subunits.

Phenylketonuria in Pediatric Neurology Practice: A Series of 146 Cases

The neurologic manifestations of patients with phenylketonuria treated at different ages are illustrated in this series of 146 cases, including 9 sib pairs. In addition to well-known findings such as mental retardation, autistic features, microcephaly, and tremor, motor retardation was common and responded promptly to dietary treatment. Hypotonia and diminished reflexes were more frequent findings than hypertonia. Four sib pairs showed divergent features, such as the later-treated sibling having higher function than the early-treated one. Because siblings have a similar genotype and similar environmental and dietary conditions, this observation can be explained by differences in phenylalanine transport to the brain or additional metabolic or perinatal factors influencing the neurologic outcome. (J Child Neurol 2006;21:987—990; DOI 10.2310/7010.2006.00228).

Mucopolysaccharidosis Type IIID: 12 New Patients and 15 Novel Mutations

Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N‐acetylglucosamine‐6‐sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported. The clinical phenotype of 12 new MPS IIID patients from 10 families was studied. Mutation analysis of GNS was performed in 16 patients (14 index cases). Clinical signs and symptoms of the MPS IIID patients appeared to be similar to previously described patients with MPS III. Early development was normal with onset of behavioral problems around the age of 4 years, followed by developmental stagnation, deterioration of verbal communication and subsequent deterioration of motor functions. Sequence analysis of the coding regions of the gene encoding GNS (GNS) resulted in the identification of 15 novel mutations: 3 missense mutations, 1 nonsense mutation, 4 splice site mutations, 3 frame shift mutations, 3 large deletions and 1 in‐frame small deletion. They include the first missense mutations and a relatively high proportion of large rearrangements, which warrants the inclusion of quantitative techniques in routine mutation screening of the GNS gene.

Valproate-induced lethal hyperammonaemic coma in a carrier of ornithine carbamoyltransferase deficiency

and 19 hours of peritoneal dialysis. The latter was accomplished by the insertion of a polyurethane catheter with a guide wire and the infusion of 25 ml/kg of 1.5% glucose dialysate per hour that was subsequently drained for 10 minutes. A total of 158mg of glycine (mean 8.3 rag/h) was removed by peritoneal dialysis. The plasma gtycine was reduced to 11.2mg/dl; thus our concerted efforts resulted in a marked reduction of plasma glycine, which still remained elevated. The clinical symptoms persisted, the EEG deteriorated and the neonate died. It is possible, however, that earlier institution of peritoneal dialysis in combination with drug administration, e.g. benzoate or strychnine, which were not available in our case, may be helpful particularly in the milder phenotypes of the disorder.

Maple syrup urine disease: Mutation analysis in Turkish patients

Maple syrup urine disease (MSUD), the most frequently occurring organic acidaemia in Turkey, is caused by a deficiency of the activity of branched-chain keto acid dehydrogenase enzyme (BCKAD) complex. Mutation analysis of the E1α, E1β, and E2 genes of the BCKAD complex in 12 Turkish MSUD patients yielded three disease-specific mutations and a polymorphism in the E1α gene, none in the E1β gene and one mutation in the E2 gene. Among them, three missense mutations (Q80E, C213Y, T106M) and the F280F polymorphism occurring in the E1α gene and the splice site mutation (IVS3 − 1G > A) in the E2 gene were novel. Three of the missense mutations and the splicing mutation occurred homozygously and caused classical MSUD. One patient carried the splicing mutation homozygously and the T106M mutation in the heterozygous state; this patient is the first case having simultaneously two different mutations in two different genes in the BCKAD complex. IVS3 − 1G > A splicing mutation detected on the E2 gene causes deletion of the first 14 bp of exon 3 in the mutant mRNA extending between 190 and 204 nt. The deletion spans the cleavage point between mitochondrial targeting and lipoyl-bearing site of the E2 protein.

Infantile spasms as the initial symptom of biotinidase deficiency

Two patients with biotinidase deficiency had diagnoses of infantile spasms made at 1 month of age. Biotinidase deficiency may be seen early in the neonatal period without the characteristic findings such as alopecia and seborrheic dermatitis. This diagnosis should be considered in patients with infantile spasms.