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Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.

ABSTRACT: Human mitochondrial trifunctional protein (TFP) is a heterooctamer of four alpha- and four beta-subunits that catalyzes three steps in the beta-oxidation spiral of long-chain fatty acids. TFP deficiency causes a Reye-like syndrome, cardiomyopathy, or sudden, unexpected death. We delineated the molecular basis for TFP deficiency in two patients with a unique phenotype characterized by chronic progressive polyneuropathy and myopathy without hepatic or cardiac involvement. Single-stranded conformation variance and nucleotide sequencing identified all patient mutations in exon 9 of the alpha-subunit. One patient is homozygous for the T845A mutation that substitutes aspartic acid for valine at residue 246. The second patient is a compound heterozygote for the T914A that substitutes asparagine for isoleucine at residue 269 and a C871T that creates a premature termination at residue 255. Allele-specific oligonucleotide hybridization studies revealed undetectable levels of the mRNA corresponding to the mutant allele carrying the termination codon. This study suggests a novel genotype-phenotype correlation in TFP deficiency; that is, mutations in exon 9 of the alpha-subunit, which encodes a linker domain between the NH2-terminal hydratase and the COOH-terminal 3-hydroxyacyl-CoA dehydrogenase, result in a unique neuromuscular phenotype.

SUBMITTER: Ibdah JA

PROVIDER: S-EPMC509102 | biostudies-other | 1998 Sep

REPOSITORIES: biostudies-other

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Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.

Ibdah J A JA Tein I I Dionisi-Vici C C Bennett M J MJ IJlst L L Gibson B B Wanders R J RJ Strauss A W AW

The Journal of clinical investigation 19980901 6

Human mitochondrial trifunctional protein (TFP) is a heterooctamer of four alpha- and four beta-subunits that catalyzes three steps in the beta-oxidation spiral of long-chain fatty acids. TFP deficiency causes a Reye-like syndrome, cardiomyopathy, or sudden, unexpected death. We delineated the molecular basis for TFP deficiency in two patients with a unique phenotype characterized by chronic progressive polyneuropathy and myopathy without hepatic or cardiac involvement. Single-stranded conformat ...[more]

PMID: 9739053

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Project description:Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic variants and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype in a mouse model of CMT4C, emphasizing the need for natural history studies to inform clinical trial readiness. Data, including both genetic information and clinical characteristics, were compiled from the longitudinal, prospective dataset of the Inherited Neuropathy Consortium, a member of the Rare Diseases Clinical Research Network (INC-RDCRN). The Charcot Marie Tooth Neuropathy Score (CMTNS), Examination Score (CMTES) and the Rasch-weighted CMTES (CMTES-R) were used to describe symptoms, neurological examinations and neurophysiological characteristics. Standardized response means were calculated at yearly intervals and a mixed model for repeated measures was used to estimate the change in CMTES and CMTES-R over time. Fifty-six individuals (59% female), median age 27 years (range 2-67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified, including 34 unique variants, 14 of which have not previously been published. Twenty-eight participants had longitudinal data available. While there was no significant difference in the CMTES in those with protein truncating versus non-protein truncating variants, there were significant differences in the mean ulnar nerve compound muscle action potential amplitude, the mean radial sensory nerve action potential amplitude, and in the prevalence of scoliosis, suggesting the possibility of a milder phenotype in individuals with one or two non-protein-truncating variants. Overall, the mean value of the CMTES was 13, reflecting moderate clinical severity. There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants. The CMTES and CMTES-R appeared moderately responsive to change over extended follow-up, demonstrating a standardized response mean of 0.81 standard deviation units or 0.71 standard deviation units, respectively, over 3 years. Our analysis represents the largest cross-sectional and only longitudinal study to date, of the clinical phenotype of both adults and children with CMT4C. With the promise of upcoming genetic treatments, these data will further define the natural history of the disease and inform study design in preparation for clinical trials.

Project description:BackgroundGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common X-linked inherited erythroenzymopathy in Thailand. The clinical and hematological manifestations of G6PD deficiency are variable.ObjectiveThis study aimed to characterize the genotype-phenotype correlation of G6PD mutations in Thai pediatric patients who were followed-up in Phramongkutklao Hospital, a tertiary center in central Thailand. Material and Method. A total of 102 children including 73 males (71.6%) and 29 females (28.4%) were included in our study. Mutation analysis was performed by direct DNA sequencing of all coding exons of the G6PD gene. Ninety-one patients (89.2%) were presented with neonatal hyperbilirubinemia and 11 patients (10.8%) were presented with acute hemolytic anemia beyond the neonatal period.ResultsMolecular analysis of the G6PD gene in 102 G6PD-deficient Thai children identified 12 different mutations. G6PD Viangchan (871G?>?A) and G6PD Canton (1376G?>?T) were the first (46.2%) and the second (15.4%) most common identified mutations among both male and female G6PD-deficient individuals, respectively. All affected males were hemizygous for G6PD mutations and had an average G6PD level of 16.7?±?11.5 (3-76) IU/ml.RBC. Majority of female patients (27 in 29, 93.1%) were heterozygous for G6PD mutations and had an average G6PD level of 133.6?±?43.4 (9-195) IU/ml.RBC. Two female patients (6.9%) were either homozygous or compound heterozygous for the mutations and had G6PD level in the affected male range (35 and 10 IU/ml.RBC). Only 1 in 27 heterozygous females (3.7%) had G6PD level in the affected male range (9 IU/ml.RBC) which is possibly explained by nonrandom X-chromosome inactivation. The correlation of genotypes, G6PD levels, and clinical phenotypes was not demonstrated in our study in which all of the included G6PD-deficient patients were presented with neonatal hyperbilirubinemia and acute hemolytic anemia, since the genotype-phenotype correlation is normally demonstrated in chronic nonspherocytic hemolytic anemia (CNSHA) G6PD-deficient individuals.ConclusionThis study characterizes the molecular heterogeneity of G6PD variants causing G6PD deficiency in Thai children. Our study demonstrated the efficiency of direct DNA sequencing which can identify 12 missense mutations in Thai children.

Dataset Information

Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.

Publications

Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.

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