Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype.

Pyruvate dehydrogenase complex (PDC) deficiency is a relatively common mitochondrial disorder that primarily presents with neurological manifestations and lactic acidemia. We analyzed the clinical outcomes and neurological features of 59 consented symptomatic subjects (27 M, 32 F), who were confirmed to have PDC deficiency with defined mutations in one of the genes of PDC (PDHA1, n = 53; PDHB, n = 4; DLAT, n = 2), including 47 different mutations, of which 22 were novel, and for whom clinical records and/or structured interviews were obtained. 39% of these subjects (23/59) have died. Of these, 91% (21/23) died before age 4 years, 61% (14/23) before 1 year, and 43% (10/23) before 3 months. 56% of males died compared with 25% of females. Causes of death included severe lactic acidosis, respiratory failure, and infection. In subjects surviving past 6 months, a broad range of intellectual outcomes was observed. Of 42 subjects whose intellectual abilities were professionally evaluated, 19% had normal or borderline intellectual ability (CQ/IQ ≥ 70), 10% had mild intellectual disability (ID) (CQ/IQ 55-69), 17% had moderate ID (CQ/IQ 40-54), 24% had severe ID (CQ/IQ 25-39) and 33% had profound ID (CQ/IQ<25). Assessment by parents was comparable. Of 10 subjects who reached age 12 years, 9 had had professional IQ assessments, and only 4 had IQs ≥ 70 (only 2 of these 4 had assessments after age 12 years). The average outcome for females was severe-to-profound ID, whereas that of males was mild-to-moderate ID. Of subjects for whom specific neurological data were available, the majority had hypotonia (89%), and hypertonia or mixed hyper-/hypotonia (49%) were common. Seizures (57%), microcephaly (49%), and structural brain abnormalities including ventriculomegaly (67%) and agenesis, dysgenesis, or hypoplasia of the corpus callosum (55%) were common. Leigh syndrome was found in only 35%. Structural brain abnormalities were more common in females, and Leigh syndrome was more common in males. In a subgroup of 16 ambulatory subjects >3.5 years in whom balance was evaluated, ataxia was found in 13. Peripheral neuropathy was documented in 2 cases but not objectively evaluated in most subjects. Outcomes of this population with genetically confirmed PDC deficiency are heterogeneous and not distinctive. Correlations between specific genotypes and outcomes were not established. Although more females survive, related to the prevalence of X-linked PDHA1 mutations, symptomatic surviving females are generally more severely impaired cognitively and have a different pattern of neurological impairment compared to males. Neonatal or infant onset of symptoms was associated with poor outcomes. Males with PDHA1 mutations and low fibroblast PDC activity were less likely to survive beyond infancy. Recurrence rate in siblings of subjects with PDHA1 mutation was less than 5%. Paradoxically, in this retrospective review, potential factors considered possibly relevant to development, such as in vitro PDC activity, specific mutations, use of ketogenic diets, supplements, or medications, were generally not confirmed to be significantly correlated with objective outcomes of survival or neuro-cognitive function. Therefore, the basis of variability of these outcomes remains largely undetermined.

Steatorrhea Versus Normal Stool in Neonatal and Early Infantile Period: Implications for Biliary Atresia.

Physicochemical property of undigested milk fat is theoretically analyzed. With uniqueness of neonatal/early infantile period and fat amount, the highest estimated stiffness of stool is gel or paste level. Therefore, typical stool of breastfed, small amount either watery or "seedy" is incompatible with steatorrhea, which may be useful to diagnose biliary atresia patients.

Silent exonic mutation in the acid-alpha-glycosidase gene that causes glycogen storage disease type II by affecting mRNA splicing.

Glycogen-storage disease type II (GSDII) is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA). The residual GAA activity is largely related to the severity of the clinical course. Most patients with infantile-onset GSDII do not show any enzyme activity, whereas patients with the late-onset forms of GSDII show various degrees of GAA activity. We performed a molecular genetic study on a Japanese boy with childhood-onset GSDII. The patient was a compound heterozygote for a newly discovered splice-site c.546G>T mutation and a recurrent missense p.R600C mutation, which usually causes the fatal infantile form in a homozygous state. The c.546G>T mutation, which did not alter the amino-acid sequence, was positioned at the last base of exon 2. cDNA-sequencing analysis revealed that c.546G>T was a leaky splice mutation, leading to the production of a normally spliced transcript, which was responsible for the low-level (approximately 10%) expression of the active enzyme in the patient's fibroblasts.

A case of primary familial congenital polycythemia with a novel EPOR mutation: possible spontaneous remission/alleviation by menstrual bleeding.

A 10-year-old girl with persistent erythrocytosis and ruddy complexion was diagnosed with primary familial congenital polycythemia (PFCP) involving a novel heterozygous mutation of c.1220C>A, p.Ser407X in exon 8 of the erythropoietin receptor gene (EPOR). This mutation causes truncation of EPOR, resulting in loss of the cytoplasmic region, which is necessary for negative regulation of erythropoietin signal transmission. Genetic analysis showed that the mutated EPOR was inherited from her mother. Her mother had polycythemia and had undergone venesection several times when she was young, but her polycythemic state appeared to have resolved. Venesection was not needed to maintain Hct levels within normal range. For the case reported here, venesection was also conducted to maintain the blood Hct level below 50%. We observed that after the patient experienced menarche, the volume and frequency of venesection needed to maintain Hct level < 50% were clearly reduced compared with those before menarche. These findings suggest that, in female patients with this type of EPOR mutation, menstruation might reduce blood volume in a manner similar to venesection. Spontaneous remission of erythrocytosis may thus occur after the start of menstrual bleeding.

Novel compound heterozygous mutations in DYNC2H1 in a patient with severe short-rib polydactyly syndrome type III phenotype.

Short-rib polydactyly syndrome type III is an autosomal recessive lethal skeletal ciliopathy, which is phenotypically similar to nonlethal asphyxiating thoracic dystrophy. Mutations in DYNC2H1 have been identified in both of these disorders, indicating that they are variants of a single disorder. However, short-rib polydactyly syndrome type III is the more severe variant. Here, we report novel compound heterozygous mutations in DYNC2H1 (p.E1894fsX10 and p.R3004C) in a patient with typical short-rib polydactyly syndrome type III phenotype. R3004 is located within the microtubule-binding domain of DYNC2H1, and its substitution is predicted to disrupt the interaction with microtubules. Considering the severe phenotype of our patient, our findings suggest that R3004 may be a key residue for the microtubule-binding affinity of dynein.

Three craniosynostotic patients with tracheal sleeve.

The gene was analysed in three craniosynostotic patients with a tracheal sleeve and other abnormalities. Although the majority of mutations are found in either exons IIIa or IIIc, this was not found in this study. It may be that patients with a tracheal sleeve are genetically heterogeneous.

A haploinsufficiency of FOXG1 identified in a boy with congenital variant of Rett syndrome.

BACKGROUND: Forkhead box G1 gene (FOXG1) mutations and deletions are associated with a congenital variant of Rett syndrome (RTT). Nucleotide alterations of the coding region of FOXG1 have never caused dysmorphic features. PATIENT: An 8-year-old boy with the congenital variant of RTT who showed severe psychomotor deterioration, epilepsy, acquired microcephaly, and involuntary movements including jerky movements of the upper limbs and tongue protrusion. He showed dysmorphic features including round face, anteverted nostrils, and tented upper lips. Brain magnetic resonance imaging showed hypoplasia of the frontal lobes and the rostral part of the corpus callosum. The molecular cytogenetic analysis confirmed a de novo deletion of 14q12 including FOXG1 in this patient. CONCLUSION: We identified the smallest deletion of 14q12 involving FOXG1 among those previously reported. Dysmorphic facial features are a characteristic for the patients with chromosomal deletion including FOXG1. In our patient, C14orf23 is the only transcript other than FOXG1. Therefore, C14orf23 might be responsible for facial dysmorphism.

Somatic mosaicism in a male with an exon skipping mutation in PDHA1 of the pyruvate dehydrogenase complex results in a milder phenotype.

Pyruvate dehydrogenase complex (PDC) deficiency is commonly due to mutations of PDHA1 on the X chromosome. Milder phenotypic manifestations occur in heterozygous females than in hemizygous males with the same mutation, and females are more likely to survive with severe mutations. The boy described here had hypotonia, moderate developmental delay, tremors, normal growth and brain MRI, and normal to slightly elevated lactate. PDC activity was low in skin fibroblasts and skeletal muscle (27-37%) but normal in lymphocytes. PDHA1 cDNA from cultured fibroblasts revealed two populations, one normal, the other lacking exon 6 (c.511-603 del). Genomic DNA from fibroblasts contained both normal and mutant (g.592G-->A) sequences within exon 6. Expression of minigene constructs containing exons 5, 6, and 7 with or without this mutation in 293T cells confirmed that the mutation alters splicing of exon 6. The mutant to wild-type DNA ratio varied substantially across tissues. Immunoblotting of fibroblast lysates detected only wild-type E1alpha protein. Immunocytochemistry of cultured skin fibroblasts showed a mosaic pattern with 60% of cells positive for E1alpha and 40% negative, consistent with PDC activity and DNA analysis. Karyotyping, FISH analyses, and genotyping revealed a 46XY male without chimerism. These data indicate somatic mosaicism for a mutation within exon 6 that causes exon skipping and production of a non-functional protein. The mutated 592G residue is conserved among all eukaryotes. Substituting A for G apparently alters normal splicing by creating a SRp40 exonic splice enhancer site. The milder phenotype in this male is accounted for by the mixture of normal cells and cells lacking E1alpha. Immunocytochemistry was a useful adjunct to molecular analysis for demonstrating mosaicism.

Clinical and biochemical findings of a patient with thanatophoric dysplasia type I: additional finding of dicarboxylic aciduria.

OBJECTIVE: A long-surviving thanatophoric dysplasia type I patient to age of 6 years is presented. RESULTS AND CONCLUSIONS: Molecular studies revealed a heterozygous point mutation, S249C in the fibroblast growth factor receptor 3 gene. Most of the clinical course was similar to previous reports, including hearing loss and acanthosis nigricans. Abnormal urinary excretion of dicarboxylic acids and 3-hydroxydicarboxylic acids was observed. We hypothesize that this was a consequence of the FGFR3 mutation.