Peripheral neuropathy, episodic myoglobinuria, and respiratory failure in deficiency of the mitochondrial trifunctional protein

Mitochondrial trifunctional protein (TFP) deficiency is a rare disorder of the fatty acid beta-oxidation cycle with heterogeneous phenotypes and occurs secondary to either alpha- or beta-subunit mutations. We characterized the neuromyopathic phenotype of TFP deficiency through adolescence or adulthood in 11 patients, 8 with beta-subunit mutations and 3 with alpha-subunit mutations. Two independent clinical features occurred: infantile-onset progressive peripheral neuropathy and episodic exercise-, illness- or fasting-induced rhabdomyolysis accompanied by respiratory failure (in five patients). The combination of episodic rhabdomyolysis and peripheral neuropathy occurred in 10 of the 11 patients. The neuromyopathic phenotype is common in TFP deficiency (11 of 27 families from our cohort). Therefore, this disorder must be considered in the differential diagnosis of progressive peripheral neuropathy with or without episodic myoglobinuria.     

Trifunctional enzyme deficiency: Adult presentation of a usually fatal β-oxidation defect

Disorders of mitochondrial fatty acid oxidation are a common cause of exercise-induced rhabdomyolysis and myoglobinuria. We report three adult patients from a family with symptoms of recurrent exercise-induced rhabdomylysis. This presentation closely resembles adult-type carnitine palmitoyltransferase II deficiency except that these patients had an associated peripheral neuropathy. Investigation of fatty acid oxidation in the patients revealed a deficiencyof the mitochondrial trifunctional enzyme of β-oxidation, a newly described fatty acid oxidation disorder with multiorgan involvement and a usually fatal outcome in early childhood. Our cases therefore represent a new phenotype of the disease, which is characterized by recurrent rhabdomyolysis and peripheral neuropathy, but without involvement of other organs, and which is associated with prolonged survival beyond the fourth decade. A low-fat/high-carbohydrate diet proved bneficial in one of the patients, drastically reducing the frequency of rhabdomyloytic episodes. Our findings suggest that mitochondrial trifnctional enzyme deficiency should be considered in patients with recurrent eipsodes of myoglobinuria and peripheral neuropathy presenting in later life.     

Myopathy with MTCYB mutation mimicking Multiple Acyl-CoA Dehydrogenase Deficiency

We describe two patients with mitochondrial DNA mutations in the gene encoding cytochrome b (m.15579A>G, p.Tyr278Cys and m.15045G>A p.Arg100Gln), which presented as a pure myopathic form (exercise intolerance), with an onset in childhood. Diagnosis was delayed, because acylcarnitine profile showed an increase in medium and long-chain acylcarnitines, suggestive of multiple acyl-CoA dehydrogenase deficiency, riboflavin transporter deficiency or FAD metabolism disorder. Implication of cytochrome b in fatty acid oxidation, and physiopathology of the mutations are discussed.     

Clinical spectrum of AIFM1‐associated disease in an Irish family,from mild neuropathy to severe cerebellar ataxia with colour blindness

Mutations in apoptosis‐inducing factor mitochondrion‐associated‐1 (AIFM1) cause X‐linked peripheral neuropathy (Cowchock syndrome, CMT4X); however, more recently a cerebellar presentation has been described. We describe a large Irish family with seven affected males. They presented with a variable age of onset, 18 months to 39 years of age. All developed variably present sensorineural deafness, peripheral neuropathy, cerebellar ataxia, and pyramidal involvement. In addition, three had colour vision deficiency. Scale for the assessment and rating of ataxia ranged 2 to 23/40, while Charcot‐Marie‐Tooth neuropathy score 2 varied between 7 and 13/36. All individuals had normal cognitive assessment. Neurophysiology demonstrated length‐dependent large‐fibre sensorimotor axonal neuropathy, with particular involvement of superficial radial sensory responses. Brain imaging, performed in four, revealed varying extent of cerebellar atrophy, and white matter changes in one. Optical coherence tomography was abnormal in one, who had unrelated eye pathology. Four obligate female carriers were assessed clinically, two of them neurophysiologically; all were unaffected. Whole genome sequencing demonstrated a previously reported hemizygous AIFM1 mutation. Analysis for mutations in other genes associated with colour deficiency was negative. AIFM1‐associated phenotype in this family demonstrated significant variability. To our knowledge, this is the first report of AIFM1‐associated colour blindness. Superficial radial nerve was particularly affected neurophysiologically, which could represent a phenotypic marker towards this specific genetic diagnosis.     

POLG mutations presenting as Charcot‐Marie‐Tooth disease

We report on two patients, with different POLG mutations, in whom axonal neuropathy dominated the clinical picture. One patient presented with late onset sensory axonal neuropathy caused by a homozygous c.2243G>C (p.Trp748Ser) mutation that resulted from uniparental disomy of the long arm of chromosome 15. The other patient had a complex phenotype that included early onset axonal Charcot‐Marie‐Tooth disease (CMT) caused by compound heterozygous c.926G>A (p.Arg309His) and c.2209G>C (p.Gly737Arg) mutations.     

Fulminant lipid storage myopathy due to multiple acyl‐coenzyme a dehydrogenase deficiency

Introduction: The lipid storage myopathies, primary carnitine deficiency, neutral lipid storage disease, and multiple acyl coenzyme A dehydrogenase deficiency (MADD), are progressive disorders that cause permanent weakness. These disorders of fatty acid metabolism and intracellular triglyceride degradation cause marked fat deposition and damage to muscle cells. Methods: We describe a rapidly progressive myopathy in a previously healthy 33‐year‐old woman. Over 4 months, she developed a proximal and axial myopathy associated with diffuse myalgia and dysphagia, ultimately leading to respiratory failure and death. Results: Muscle biopsy showed massive accumulation of lipid. Plasma acylcarnitine and urine organic acid analysis was consistent with MADD. This was confirmed by molecular genetic testing, which revealed 2 pathogenic mutations in the ETFDH gene. Conclusions: This report illustrates a late‐onset case of MADD and reviews the differential diagnosis and evaluation of patients with proximal myopathy and excessive accumulation of lipid on muscle biopsy. Muscle Nerve 52 : 289–293, 2015     

Disorders of muscle lipid metabolism: Diagnostic and therapeutic challenges

Disorders of muscle lipid metabolism may involve intramyocellular triglyceride degradation, carnitine uptake, long-chain fatty acids mitochondrial transport, or fatty acid β-oxidation. Three main diseases leading to permanent muscle weakness are associated with severe increased muscle lipid content (lipid storage myopathies): primary carnitine deficiency, neutral lipid storage disease and multiple acyl-CoA dehydrogenase deficiency. A moderate lipidosis may be observed in fatty acid oxidation disorders revealed by rhabdomyolysis episodes such as carnitine palmitoyl transferase II, very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein deficiencies, and in recently described phosphatidic acid phosphatase deficiency. Respiratory chain disorders and congenital myasthenic syndromes may also be misdiagnosed as fatty acid oxidation disorders due to the presence of secondary muscle lipidosis. The main biochemical tests giving clues for the diagnosis of these various disorders are measurements of blood carnitine and acylcarnitines, urinary organic acid profile, and search for intracytoplasmic lipid on peripheral blood smear (Jordan’s anomaly). Genetic analysis orientated by the results of biochemical investigation allows establishing a firm diagnosis. Primary carnitine deficiency and multiple acyl-CoA dehydrogenase deficiency may be treated after supplementation with carnitine, riboflavine and coenzyme Q10. New therapeutic approaches for fatty acid oxidation disorders are currently developed, based on pharmacological treatment with bezafibrate, and specific diets enriched in medium-chain triglycerides or triheptanoin.     

Ultrasound imaging for diagnosis and follow‐up of persistent median artery thrombosis

Introduction: Adult‐onset Krabbe disease is clinically rare and usually affects the pyramidal tracts in the central nervous system. Patients develop a spastic gait, and peripheral neuropathy sometimes occurs simultaneously. Methods: A 55‐year‐old woman with consanguineous parents developed slowly progressive, asymmetric muscle weakness and atrophy in her forearms, while her ability to walk remained unaffected without pyramidal tract signs after onset at age 51 years. Results: Nerve conduction studies demonstrated an asymmetric demyelinating‐type peripheral neuropathy, and sural nerve biopsy documented reduced myelinated nerve fiber density with uniformly thin myelin sheaths, suggesting hypomyelination. Brain MRI demonstrated minor white‐matter injury along the optic radiations, which was associated with asymptomatic, mild, prolonged latency on visual evoked potentials. Laboratory analysis documented low enzyme activity of galactocerebrosidase (GALC) and a known mutation of the GALC gene. Conclusion: Isolated peripheral neuropathy occurs very rarely in adult‐onset Krabbe disease. Muscle Nerve 54 : 152–157, 2016     

Recurrent central nervous system white matter changes in charcot–Marie–Tooth type X disease

Introduction: X‐linked Charcot–Marie–Tooth (CMT1X) disease is caused by mutations in the GJB1 gene. We describe a young man who presented with recurrent central nervous symptoms and transient white matter changes in the setting of a novel mutation in the GJB1 gene. Methods: Evaluation included clinical examination, neuroimaging, electrophysiological, and molecular genetic studies. Results: Clinical examination on 2 admissions 5 years apart demonstrated hemiparesis with findings of underlying peripheral neuropathy. Electrophysiologic studies revealed a sensorimotor polyneuropathy. MRI studies from both admissions revealed white matter changes, with improvement on an intervening study. Mutation analysis showed a novel mutation (c.98T>A; p.Ile33Asn) in the GJB1 gene. Conclusions: Mutations in GJB1 can result in recurrent central nervous system symptoms with transient white matter signal changes on MRI. In patients presenting with hemiparesis, the presence of signs of a peripheral neuropathy may facilitate identification of CMT1X, and is likely to affect clinical management. Muscle Nerve 49 :451–454, 2014     

A new case of short-chain acyl-CoA dehydrogenase deficiency: clinical,biochemical, genetic and <Superscript>1</Superscript>H-NMR spectroscopic studies

Short-chain-acyl-CoA-dehydrogenase (SCAD) deficiency is an inborn error of mitochondrial fatty acid metabolism caused by rare mutations as well as common susceptibility variations in the SCAD gene. We describe the case of a 23-year-old male patient who had growth and mental retardation, recurrent vomiting, fever and seizures since infancy. Urinary gas chromatography and ¹H-nuclear magnetic resonance showed elevated levels of ethylmalonic acid. Serum concentrations of acylcarnitine, especially butyrylcarnitine (C4), were abnormally high. A homozygous variant allele of the SCAD gene, 625G>A, was detected. The patient broadens the clinical phenotype of SCAD deficiency and underlines the difficulty of diagnosis. The limited number of patients described may be the result of underdiagnosis.     

A novel mutation in the mitochondrial tRNA for tryptophan causing a late‐onset mitochondrial encephalomyopathy

Sanaker PS, Nakkestad HL, Downham E, Bindoff LA. A novel mutation in the mitochondrial tRNA for tryptophan causing a late‐onset mitochondrial encephalomyopathy.
Acta Neurol Scand: 2010: 121: 109–113.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – Mitochondrial DNA (mtDNA) mutations are increasingly being recognized as causes of late‐onset disease. We report a patient with a late‐onset mitochondrial encephalomyopathy caused by a novel G > C transition in mtDNA at position 5556 in the gene encoding the tRNA for tryptophan (MTTW). Aims – To investigate the cause of disease and assess the pathogenicity of this new mutation. Methods – Clinical, histopathological and gene sequencing studies. Quantification of the mutation was performed in different tissues from the patient and two relatives and in single muscle fibres. Results – The mutation was heteroplasmic, segregated in biochemically affected muscle fibres and was absent in blood. The level of mutation in skeletal muscle was higher than in brain, although the brain was clinically the most affected tissue. Discussion – The 5556G > C mutation appears sporadic. It was not found in any of the family members tested, although some of them manifested disorders that can be associated with mtDNA disease. In addition to reporting the eighth mutation in MTTW, our case illustrates the challenges posed when assigning pathogenicity to mtDNA mutations.     

Early onset Charcot‐Marie‐Tooth neuropathy type 2A and severe developmental delay: expanding the clinical phenotype of MFN2‐related neuropathy

Charcot‐Marie‐Tooth (CMT) syndromes are a group of clinically heterogeneous disorders of the peripheral nervous system. Mutations of mitofusin 2 (MFN2) have been recognized to be associated with CMT type 2A (CMT2A). CMT2A is primarily an axonal disorder resulting in motor and sensory neuropathy. We report a male child with psychomotor delay, dysmorphic features, and weakness of lower limbs associated with electrophysiological features of severe, sensory‐motor, axonal neuropathy. The patient was diagnosed with early onset CMT2A and severe psychomotor retardation associated with c.310C>T mutation (p.R104W) in MFN2 gene. CMT2A should be considered in patients with both axonal sensory‐motor neuropathy and developmental delay.     

Novel mutations in the gene encoding very long‐chain acyl‐CoA dehydrogenase identified in patients with partial carnitine palmitoyltransferase ii deficiency

Introduction: Twenty‐six patients with clinical symptoms of adult onset carnitine palmitoyltransferase II (CPTII) deficiency were examined. All patients had skeletal muscle CPTII enzyme activity levels indicative of heterozygosity for CPT2 mutations, however sequence analysis identified no pathogenic mutations within the CPT2 gene. Methods: Because the reaction product of CPTII is the substrate for very long‐chain acyl‐CoA dehydrogenase (VLCAD), we examined the ACADVL gene in these patients by sequence analysis. Results: Missense mutations within the ACADVL gene were identified in 3 of the patients. Conclusions: The locations of the altered amino acid residues within the crystal structure of VLCAD are on the surface of the molecule and may be involved in interactions with neighboring molecules. These findings support the importance of considering that mutations may be present in the ACADVL gene when a significant partial deficiency is found in CPTII activity, but no mutations in the CPT2 gene can be identified. Muscle Nerve, 2013     

Importance of acylcarnitine profile analysis for disorders of lipid metabolism in adolescent patients with recurrent rhabdomyolysis: Report of two cases

Metabolic myopathies due to disorders of lipid metabolism are a heterogeneous group of diseases. Newborns may present with hypotonia and convulsions, while progressive proximal muscle weakness or recurrent episodes of muscle weakness accompanied by rhabdomyolysis/myoglobinuria may be seen in older ages. There is little knowledge on detection of disorders of lipid metabolism by acylcarnitine profile (ACP) analysis by tandem mass spectrometry outside the neonatal period particularly in cases with recurrent rhabdomyolysis first presenting in adolescence and adulthood. Two adolescent female cases presented with episodes of rhabdomyolysis and muscle weakness. A 13-year-old patient had five episodes of rhabdomyolysis triggered by infections. Tandem mass spectrometry was normal. A 16-year-old female patient was hospitalized eight times due to recurrent rhabdomyolysis. Increased levels of C14:2, C14:1, and C14 were determined in tandem mass spectrometry. Final diagnoses were carnitine palmitoyltransferase II (CPT II) deficiency and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Increased serum levels of long-chain acylcarnitine can guide to the diagnosis of lipid metabolism disorders. Serum ACP should be performed before enzyme assay and genetic studies.     

Neurofilament light mutation causes hereditary motor and sensory neuropathy with pyramidal signs

To identify novel mutations causing hereditary motor and sensory neuropathy (HMSN) with pyramidal signs, a variant of Charcot‐Marie‐Tooth disease (CMT), we screened 28 CMT and related genes in four members of an affected Japanese family. Clinical features included weakness of distal lower limb muscles, foot deformity, and mild sensory loss, then late onset of progressive spasticity. Electrophysiological studies revealed widespread neuropathy. Electron microscopic analysis showed abnormal mitochondria and mitochondrial accumulation in the neurons and Schwann cells. Brain magnetic resonance imaging (MRI) revealed an abnormally thin corpus callosum. In all four, microarrays detected a novel heterozygous missense mutation c.1166A>G (p.Y389C) in the gene encoding the light‐chain neurofilament protein (NEFL), indicating that NEFL mutations can result in a HMSN with pyramidal signs phenotype.     

Respiratory chain deficiency presenting as recurrent myoglobinuria in childhood

Myoglobinuria is an abnormal urinary excretion of myoglobin due to an acute destruction of skeletal muscle fibres. Several metabolic diseases are known to account for myoglobinuria including defects of glycolysis and fatty acid oxidation. Here, we report on respiratory chain enzyme deficiency in three unrelated children with recurrent episodes of myoglobinuria and muscle weakness (complex I: one patient, complex IV: two patients). All three patients had generalized hyporeflexia during attacks, a feature which is not commonly reported in other causes of rhabdomyolysis. Studying respiratory chain enzyme activities in cultured skin fibroblasts might help diagnosing this condition, especially when acute rhabdomyolysis precludes skeletal muscle biopsy during and immediately after episodes of myoglobinuria.     

Neuroimaging of classic neuralgic amyotrophy

Introduction: Neuralgic amyotrophy (NA) often imposes diagnostic problems. Recently, MRI and high‐resolution ultrasound (HRUS) have proven useful in diagnosing peripheral nerve disorders. Methods: We performed a chart and imaging review of patients who were examined using neuroimaging and who were referred because of clinically diagnosed NA between March 1, 2014 and May 1, 2015. Results: Six patients were included. All underwent HRUS, and 5 underwent MRI. Time from onset to evaluation ranged from 2 weeks to 6 months. HRUS showed segmental swelling of all clinically affected nerves/trunks. Atrophy of muscles was detected in those assessed >1 month after onset. MRI showed T2‐weighted hyperintensity in all clinically affected nerves, except for the long thoracic nerve, and denervation edema of muscles. Conclusions: HRUS and MRI are valuable diagnostic tools in NA. This could change the diagnostic approach from one now focused on excluding other disorders to confirming NA through imaging markers. Muscle Nerve 54 : 1079–1085, 2016     

Mutational screening of the SH3TC2 gene in Greek patients with suspected demyelinating recessive Charcot‐Marie‐Tooth disease reveals a varied and unusual phenotypic spectrum

Charcot‐Marie‐Tooth disease type 4 C (CMT4C) is an autosomal recessive form of demyelinating peripheral neuropathy caused by mutations in SH3TC2, characterized by early onset, spine deformities, and cranial nerve involvement. We screened SH3TC2 in 50 unrelated Greek patients with suspected demyelinating Charcot‐Marie‐Tooth disease and pedigree compatible with recessive inheritance. All patients had been previously screened for PMP22, GJB1, and MPZ mutations. We found five previously identified pathogenic mutations in SH3TC2 distributed among 13 patients in homozygosity or compound heterozygosity (p. Arg954Stop, Arg1109Stop, Gln892Stop, Ala878Asp, and Arg648Trp). Although most cases had early onset and spine deformities were almost omnipresent, a wide phenotypic spectrum was observed. Particularly notable were two siblings with Roussy‐Lévy syndrome and one patient with young‐onset trigeminal neuralgia. In conclusion, mutations in SH3TC2 are responsible for 26% of Greek patients with suspected CMT4, identifying CMT4C as the most common recessive demyelinating neuropathy in the Greek population, in accordance with other Mediterranean cohorts.     

Unusual features of central nervous system involvement in CMTX associated with a novel mutation of GJB1 gene

In this study, we report a novel connexin 32 (CX32) mutation associated with cognitive impairment and a differential degree of peripheral nerve involvement. We present clinical, electrophysiological, and neuroimaging data on a family with X‐linked Charcot‐Marie‐Tooth disease caused by a 41A>G mutation of the gap junction protein beta 1 (GJB1) gene. The proband and her sister presented with a severe neuropathy with subclinical cognitive impairment; the proband's brother showed severe cognitive impairment and a mild neuropathy. This family report confirms that Charcot‐Marie‐Tooth type X is a clinically heterogeneous group, with great variability of phenotypes, possible severe involvement in females and clinical signs of cognitive impairment. Thus, this novel mutation should be added to the group of CX32 mutations with a central nervous system phenotype.