Multisystem involvement in Chinese patients with neuromyopathic phenotype of mitochondrial trifunctional protein deficiency.
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ABSTRACT:
SUBMITTER: Wei CJ
PROVIDER: S-EPMC7289308 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
Multisystem involvement in Chinese patients with neuromyopathic phenotype of mitochondrial trifunctional protein deficiency.
Wei Cui-Jie CJ Chang Xing-Zhi XZ Ge Lin L Fu Xiao-Na XN Fan Yan-Bin YB Liu Jie-Yu JY Wang Shuang S Li Hai-Li HL Yang Yan-Ling YL Xiong Hui H
Chinese medical journal 20200601 11
Similar Datasets
Project description:Axonal peripheral neuropathy is a common complication of mitochondrial trifunctional protein (MTP) deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency that is usually considered progressive. Current treatment strategies are not able to fully prevent neuropathic symptoms in the majority of patients. We herein report three sisters with genetically proven MTP deficiency who were untreated until adolescence, when electrophysiological studies first revealed isolated axonal sensory neuropathy. Apart from mild exercise intolerance and missing deep tendon reflexes of the lower extremities, all three girls were clinically asymptomatic. A fat-reduced and fat-modified diet together with a reduction of the nocturnal fasting time resulted in complete normalisation of the electrophysiological studies after 1 year of dietary treatment. Our findings suggest that neuropathy might be responsive to dietary interventions in MTP patients at a very early stage of disease.
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Project description:We report an 8-year-old girl with lower limb weakness since birth in whom mitochondrial trifunctional protein (MTP) deficiency, an autosomal recessive fatty acid oxidation disorder caused by HADHA or HADHB mutations, had not been definitively diagnosed before she was referred to our hospital. Repeated blood acylcarnitine analysis revealed slightly increased long-chain 3-OH-acylcarnitine levels; electromyography (EMG) suggested peripheral nerve injury; muscle biopsy confirmed a neurogenic lesion in muscle fibers, as shown by EMG. Analysis of the HADHB, which encodes long-chain 3-ketoacyl-CoA thiolase, one of the enzymes constituting mitochondrial trifunctional protein, identified homozygous missense mutation c.739C > T (p.R247C). Mitochondrial trifunctional protein deficiency is an extremely rare disorder and has not been reported in Chinese people to date. It is likely that neonatal onset, as seen in our patient, has not been reported for the neuromyopathic phenotype of mitochondrial trifunctional protein deficiency.
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Project description:Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.
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Project description:We describe mitochondrial trifunctional protein deficiency (MTPD) in two male siblings who presented with severe cardiomyopathy in infancy. The first sibling presented in severe cardiac failure at 6 months of age and succumbed soon after. The second sibling came to attention after newborn screening identified a possible fatty acid oxidation defect. Dietary therapy and carnitine supplementation commenced in the neonatal period. Despite this the second child required cardiac transplantation at 3 years of age after a sudden and rapid decline in cardiac function. The outcome has been excellent, with no apparent extra-cardiac manifestations of a fatty acid oxidation disorder at the age of 7. Pathogenic HADHA mutations were subsequently identified via genome wide exome sequencing. This is the first reported case of MTPD to undergo cardiac transplantation. We suggest that cardiac transplantation could be considered in the treatment of cardiomyopathy in MTPD.
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Project description:Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid β-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2-10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6-18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.
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Project description:We encountered a patient with mitochondrial trifunctional protein deficiency in whom the corresponding mutations were not identified by a DNA panel for newborn screening for targeted diseases. After diagnosis confirmation by an enzyme assay and immunoblotting using the autopsied liver, the re-evaluation of the panel data indicated a heterozygous deletion of exons 6-9 that was later confirmed at the genomic level. cDNA analysis also identified exonization of the 5' region of intron 9 caused by a deep intronic mutation, c.811 + 82A>G.
| S-EPMC7118068 | biostudies-literature
Project description:Trifunctional protein deficiency (TFP) is a disorder of fatty acid beta-oxidation associated with metabolic, cardiac, and liver dysfunction in severe forms. We present two siblings diagnosed by newborn screening and confirmed by biochemical testing at birth. Their clinical course was complicated by recurrent rhabdomyolysis, retinopathy, and hypoparathyroidism. Both siblings were also diagnosed with focal segmental glomerulosclerosis (FSGS) and bone marrow failure and ultimately died of hypoxemic respiratory failure. Initial sequencing of the TFP-associated genes HADHA and HADHB showed only a paternally inherited variant in HADHB, NM_000183.3:c.1059del (p.Gly354AspfsTer10). Subsequent evaluation by the Undiagnosed Diseases Network with genome and transcriptome sequencing revealed a rare maternally inherited 17 base pair deletion in HADHB, NM_000183.3:c.1390-515_1390-499del, located in the final intron and resulting in a pseudoexon that harbors a premature termination codon. Both sisters were compound heterozygous for this and the paternal premature termination codon. No other variants were detected that were potentially causative for the FSGS and bone marrow failure on genome sequencing. A review of the literature at that time revealed several case reports of the uncommon clinical findings of FSGS, bone marrow failure, and pulmonary involvement in patients with TFP, confirming this clinical diagnosis as the complete explanation for these siblings.
| S-EPMC11667764 | biostudies-literature
Project description:A combination of unexplained peripheral neuropathy, hypoparathyroidism, and the inability to cope with metabolic stress could point to a rare inborn error of metabolism, such as mitochondrial trifunctional protein (MTP) deficiency.Here, we describe a 20-year-old woman who was known since childhood with axonal motor sensory polyneuropathy of unknown origin. She presented with progressive dyspnoea, and increased muscle weakness, preceded by 6 days of fever, vomiting, and diarrhoea. Laboratory testing showed rhabdomyolysis, and hypocalcaemia with low parathyroid levels. The patient was intubated because of respiratory insufficiency and a viral and bacterial pneumonia was diagnosed. She was discharged after 16 days of admission. Metabolic screening, performed at the time of rhabdomyolysis, showed increased concentrations of long-chain 3-hydroxyacyl carnitine species, together with elevated urinary excretion of 3-hydroxy dicarboxylic acids. Decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase in peripheral lymphocytes and fibroblasts confirmed a MTP deficiency. Sequence analysis of the HADHB gene showed two heterozygous variants: c.209+1G>C (splicing defect) and c.980T>C (p.Leu327Leu). When the acylcarnitine profile was repeated after the episode of rhabdomyolysis had resolved it showed no abnormalities.Our case illustrates a cluster of peripheral neuropathy, episodic rhabdomyolysis, and hypoparathyroidism in a patient with MTP deficiency caused by mutations in the HADHB gene. It stresses the importance of performing metabolic screening when patients are most symptomatic, as normal results can be found at times when no metabolic stress is present. Screening is relatively easy and timely diagnosis has important implications for treatment.
| S-EPMC5874207 | biostudies-literature
Project description:Deficiency of the mitochondrial trifunctional protein (TFP) and long-chain 3-Hydroxy Acyl-CoA dehydrogenase (LCHAD) impairs long-chain fatty acid oxidation and presents with hypoglycemia, cardiac, liver, eye, and muscle involvement. Without treatment, both conditions can be life-threatening. These diseases are identified by newborn screening (NBS), but the impact of early treatment on long-term clinical outcome is unknown. Moreover, there is lack of consensus on treatment, particularly on the use of carnitine supplementation. Here, we report clinical and biochemical data in five patients with TFP/LCHAD deficiency, three of whom were diagnosed by newborn screening. All patients had signs and symptoms related to their metabolic disorder, including hypoglycemia, elevated creatine kinase (CK), and rhabdomyolysis, and experienced episodes of metabolic decompensation triggered by illness. Treatment was started shortly after diagnosis in all patients and consisted of a diet low in long-chain fats supplemented with medium chain triglycerides (MCT), essential fatty acids, and low-dose carnitine (25 mg/kg/day). Patients had growth restriction early in life that resolved after 2 years of age. All patients but the youngest (2 years old) developed pigmentary retinopathy. Long-chain hydroxylated acylcarnitines did not change significantly with age, but increased during acute illnesses. Free carnitine levels were maintained within the normal range and did not correlate with long-chain hydroxylated acylcarnitines. These results show that patients with LCHAD deficiency can have normal growth and development with appropriate treatment. Low-dose carnitine supplements prevented carnitine deficiency and did not result in increased long-chain hydroxylated acylcarnitines or any specific toxicity.
| S-EPMC5388644 | biostudies-literature
Project description:BACKGROUND:Newborn screening (NBS) for long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency does not discriminate between isolated LCHAD deficiency, isolated long-chain keto acyl-CoA (LCKAT) deficiency and general mitochondrial trifunctional protein (MTP) deficiency. Therefore, screening for LCHAD deficiency inevitably comprises screening for MTP deficiency, which is much less amenable to treatment. Furthermore, absence of a clear classification system for these disorders is still lacking. MATERIALS AND METHODS:Two newborns screened positive for LCHAD deficiency died at the age of 10 and 31 days, respectively. One due to severe necrotizing enterocolitis (NEC), cardiomyopathy and multiorgan failure and the other due to severe infant respiratory distress syndrome (IRDS) and hypertrophic cardiomyopathy. (Keto)-acylcarnitine concentration and enzymatic analysis of LCHAD and LCKAT suggested MTP deficiency in both patients. Mutation analysis revealed a homozygous HADHB c.357+5delG mutation in one patient and a homozygous splice-site HADHB mutation c.212+1G>C in the other patient.Data on enzymatic and mutation analysis of 40 patients with presumed LCHAD, LCKAT or MTP deficiency were used to design a classification to distinguish between these disorders. DISCUSSION:NEC as presenting symptom in MTP deficiency has not been reported previously. High expression of long-chain fatty acid oxidation enzymes reported in lungs and gut of human foetuses suggests that the severe NEC and IRDS observed in our patients are related to the enzymatic deficiency in these organs during crucial stages of development.Furthermore, as illustrated by the cases we propose a classification system to discriminate LCHAD, LCKAT and MTP deficiency based on enzymatic analysis.
| S-EPMC3575038 | biostudies-literature