Mitochondrial trifunctional protein deficiency: A rare cause of adult‐onset rhabdomyolysis

Introduction: Mitochondrial trifunctional protein deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid β‐oxidation that may be due to mutations in 2 different nuclear genes, HADHA and HADHB. Perturbation of this multienzyme complex compromises the oxidation of long‐chain fatty acids, which leads to multiorgan dysfunction. Childhood‐ or adolescent‐onset recurrent rhabdomyolysis is a common muscular manifestation and is preceded frequently by clinically overt peripheral neuropathy. Methods: In this report we describe a patient with late adult‐onset recurrent rhabdomyolysis. Results: Despite normal sensory examination, nerve conduction studies showed a mild axonal peripheral neuropathy. The acylcarnitine profile showed elevated long‐chain and 3‐hydroxy long‐chain acylcarnitine species. HADHA sequencing revealed known compound heterozygous mutations c.180+3A>G (p.Thr37SerfsX6) and c.1528G>C (p.Glu510Gln). During a 10‐month follow‐up period, he had no further episodes of rhabdomyolysis after appropriate dietary modifications. Conclusions: Mitochondrial trifunctional protein deficiency should be considered in patients with adult‐onset recurrent rhabdomyolysis, especially in those with either clinically overt or subclinical peripheral neuropathy. Muscle Nerve 48 : 989–991, 2013     

GNAO1‐associated epileptic encephalopathy and movement disorders: c.607G>A variant represents a probable mutation hotspot with a distinct phenotype

We describe a case of GNAO1‐associated epilepsy and chorea in a patient with a de novo pathogenic mutation. This patient is unique in being the first reported male with this phenotype, and we propose that this genetic variant may represent a mutation hotspot that characterizes a unique phenotype. This 5.2‐years‐old boy presented with seizures, chorea, and severe global developmental delay. Brain imaging showed progressive diffuse cerebral atrophy. EEG monitoring revealed multifocal and diffuse discharges, along with generalized‐onset seizures. Genetic testing found a de novo pathogenic variant in the GNAO1 gene (c.607G>A; p.Gly203Arg). A review of the literature showed two other patients with similar phenotype and the same genetic variant. In contrast, other patients with neurological involvement had private mutations in the GNAO1 gene. The neurological phenotypes associated with GNAO1 mutations appear to lie on a spectrum, and it is possible that the c.607G>A (p.Gly203Arg) variant characterizes a phenotype with both severe epilepsy and chorea. [Published with video sequence on www.epilepticdisorders.com ]     

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.     

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.     

A cryptic splicing mutation in the INF2 gene causing Charcot‐Marie‐Tooth disease with minimal glomerular dysfunction

Heterozygous mutations in the inverted formin‐2 (INF2) gene provoke focal segmental glomerulosclerosis (FSGS) and intermediate Charcot‐Marie‐Tooth (CMT) disease with FSGS. Here, we report four patients from a three‐generation family with a new cryptic splicing INF2 mutation causing autosomal dominant intermediate CMT with minimal glomerular dysfunction. Three males and one female with a mean age of 51 years (26‐87) presented with a slowly progressive sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis. Mean age at CMT disease onset was 11.5 years (3‐17), and electrophysiological studies showed demyelinating and axonal features consistent with intermediate CMT. Plasma albumin and creatinine were normal in all four cases, and urine protein was normal in one case and mildly raised in three patients (mean: 0.32 g/L [0.18‐0.44], N < 0.14). Genetic analysis found a c.271C > G (p. Arg91Gly) variation in INF2 exon 2, and in vitro splicing assays showed the deletion of the last 120 nucleotides of INF2 exon 2 leading to a 40 amino acids in‐frame deletion (p. Arg91_p. Gln130del). This report expands the genetic spectrum of INF2‐associated disorders and demonstrates that INF2 mutations may provoke isolated CMT with no clinically relevant kidney involvement. Consequently, INF2 mutation analysis should not be restricted to individuals with coincident neuropathy and renal disease.     

Mutational mechanisms in MFN2‐related neuropathy: compound heterozygosity for recessive and semidominant mutations

Mitofusin‐2 (MFN2) mutations are the most common cause of autosomal dominant axonal Charcot‐Marie‐Tooth disease (CMT, type 2A), sometimes complicated by additional features such as optic atrophy (CMT6) and upper motor neuron involvement (CMT5). Several pathogenic mutations are reported, mainly acting in a dominant fashion, although few sequence variants behaved as recessive or semidominant in rare homozygous or compound heterozygous patients. We describe a 49‐year‐old woman with CMT5 associated with compound heterozygosity for two MFN2 variants, one already reported missense mutation (c.748C>T, p.R250W) and a novel nonsense sequence change (c.1426C>T, p.R476*). Her mother, carrying the p.R250W variant, had very late‐onset minimal axonal neuropathy, whilst the father harboring the nonsense sequence change had neither clinical nor electrophysiological neuropathy. The missense mutation is likely pathogenic according to in silico analyses and a previous report, while the nonsense variant is predicted to behave as a null allele. The p.R250W variant behaves as semidominant by causing only a mild, almost subclinical, neuropathy when heterozygous; the nonsense mutation in the father was phenotypically silent, suggesting that haploinsufficiency for MFN2 is not disease causative, but was deleterious in the daughter who had only one active mutated MFN2 allele.     

A novel NDRG1 mutation in a non‐Romani patient with CMT4D/HMSN‐Lom

Charcot‐Marie‐Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N‐Myc downstream‐regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38‐year‐old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating CMT.     

Heterogeneity of axonal pathology in chinese patients with giant axonal neuropathy

Introduction: Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the GAN gene. Herein we report ultrastructural changes in Chinese patients with GAN. Methods: General clinical assessment, sural nerve biopsy, and genetic analysis were performed. Results: Sural biopsy revealed giant axons in 3 patients, 2 with a mild phenotype and 1 with a classical phenotype. Ultrastructurally, all patients had giant axons filled with closely packed neurofilaments. In addition, the classical patient had some axons containing irregular tubular‐like structures. GAN mutation analysis revealed novel compound heterozygous c.98A>C and c.158C>T mutations in the BTB domain in 1 mild patient, a novel homozygous c.371T>G mutation in the BACK domain in another mild patient, and a novel c.1342G>T homozygous mutation in the Kelch domain in the classical patient. Conclusion: Closely packed neurofilaments in giant axons are common pathological changes in Chinese patients with GAN, whereas irregular tubular‐like structures appear in the classical type of this neuropathy. Muscle Nerve 50:200–205, 2014     

De novo DNM1 mutations in two cases of epileptic encephalopathy

Dynamin 1 (DNM1) is a large guanosine triphosphatase involved in clathrin‐mediated endocytosis. In recent studies, de novo mutations in DNM1 have been identified in five individuals with epileptic encephalopathy. In this study, we report two patients with early onset epileptic encephalopathy possessing de novo DNM1 mutations. Using whole exome sequencing, we detected the novel mutation c.127G>A (p.Gly43Ser) in a patient with Lennox‐Gastaut syndrome, and a recurrent mutation c.709C>T (p.Arg237Trp) in a patient with West syndrome. Structural consideration of DNM1 mutations revealed that both mutations would destabilize the G domain structure and impair nucleotide binding, dimer formation, and/or GTPase activity of the G domain. These and previous cases of DNM1 mutations were reviewed to verify the phenotypic spectrum. The main clinical features of DNM1 mutations include intractable seizures, intellectual disability, developmental delay, and hypotonia. Most cases showed development delay before the onset of seizures. A patient carrying p.Arg237Trp in this report showed a different developmental status from that of a previously reported case, together with characteristic extrapyramidal movement.     

A novel mutation in PRPS1 causes X‐linked Charcot‐Marie‐Tooth disease‐5

X‐linked Charcot‐Marie‐Tooth disease‐5 (CMTX5) is a rare hereditary disorder caused by mutations in the gene for phosphoribosyl pyrophosphate synthetase‐1 (PRPS1). We investigated a boy with a novel PRPS1 mutation (c.334G>C, p.V112L) via genetic, neuropathological and enzymatic tests. The proband was a 13‐year‐old boy with congenital non‐syndromic sensorineural deafness. At 3 year old, he developed progressive distal weakness of all limbs with muscle atrophy of both hands and shanks. Nerve conduction study revealed the loss of sensory nerve action potentials, and slowing down of motor nerve conduction velocities with a decrease of amplitudes of compound motor action potentials. Visual evoked potentials and brainstem auditory evoked potentials were not bilaterally evocable. Sural biopsy proved the loss of myelinated nerve fibers, with axonal degeneration, regenerating clusters and onion bulbs. Enzymatically, PRPS1 activity was close to zero in the proband and mildly reduced in his mother, compared with controls. To our knowledge, this is the first report of CMTX5 in a Chinese population. The genetic finding has expanded the genotypic spectrum of PRPS1 mutations.     

Late‐onset hereditary sensory and autonomic neuropathy expands the phenotypic spectrum of MFN2‐related diseases

Mutations in the Mitofusin 2 (MFN2) gene have been identified in patients with autosomal dominant axonal motor and sensory neuropathy or Charcot–Marie‐Tooth 2A (CMT2A). Here we describe clinical and pathological changes in an adult patient with sporadic hereditary sensory and autonomic neuropathy (HSAN) due to an MFN2 mutation. The patient was a 53‐year‐old man who had sensory involvement and anhidrosis in all limbs without motor features. The electrophysiological assessment documented severe axonal sensory neuropathy. The sural nerve biopsy confirmed the electrophysiological findings, revealing severe loss of myelinated and unmyelinated fibers with regeneration clusters. Genetic analysis revealed the previously identified mutation c.776 G > A in MFN2. Our report expands the phenotypic spectrum of MFN2‐related diseases. Sequencing of MFN2 should be considered in all patients presenting with late‐onset HSAN.     

Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland

Charcot–Marie–Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.     

Mitochondrial membrane protein-associated neurodegeneration: a case report and literature review

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.     

Four novel mutations in the GCH1 gene of Chinese patients with dopa‐responsive dystonia

Mutation detection in the guanosine triphosphate cyclohydrolase I gene (GCH1) was performed from 4 female patients with dopa‐responsive dystonia (DRD). DNA sequencing revealed the presence of four novel mutations including c.2T>C(M1T), c.239G>A(S80N), c.245T>C(L82P), and IVS5+3 del AAGT. These four mutations were not found in 100 genetically unrelated healthy controls with the same ethnic background band. In all 3 childhood‐onset patients, DRD started in the legs, and missense mutations were located in the coding region of GCH1. Deletion mutation in the fifth exon–intron boundary of GCH1 was detected in the adult‐onset patient. Although the data presented here do not provide sufficient evidence to establish a genotype–phenotype correlation of DRD, it is important to know the clinic features and genetic defects of DRD patients, which will help prenatal diagnosis, early diagnosis, evaluate the prognosis, and facilitate causal therapy with levodopa. © 2010 Movement Disorder Society     

Twinkle mutations in two Chinese families with autosomal dominant progressive external ophthalmoplegia

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a common adult onset mitochondrial disease caused by mutations in nuclear DNA (nDNA). Twinkle is one of the nuclear genes associated with adPEO. Clinical, histochemical, and molecular genetics findings of 6 patients from two Chinese families with adPEO were reported. Two point mutations (c.1423G>C, p.A475P and c.1061G>C, p.R354P) of Twinkle gene have been found. Multiple mtDNA deletions were also detected in patient’s muscle and fibroblasts. This study confirms two mutations in Chinese adPEO families, which were first reported in the Chinese population.     

Evolution of the phenotype in a family with an LMNA gene mutation presenting with isolated cardiac involvement

The aim of this study is to report the evolution of a phenotype in members of a single family carrying the heterozygous exon 1 c.178 C/G, p.Arg 60 Gly LMNA gene mutation. All mutated family members underwent neurological and cardiological assessments for a period ranging from 10 to 20 years. At onset, 4 affected adult members presented a phenotype that required pacemaker implantation. Three subjects underwent cardiac transplantation leading to long‐term survival in 2 of them. One of the 3 longest surviving relatives manifested late lipodystrophy, and the other 2 had lipodystrophy, insulin‐resistant diabetes, and distal peripheral neuropathy. The findings demonstrate that the exon 1 c.178 C/G, p.Arg 60 Gly LMNA gene mutation is associated with a novel phenotype featuring cardiac involvement followed by late lipodystrophy, diabetes, and peripheral axonal neuropathy. Muscle Nerve, 2010     

A de novo dominant mutation in KIF1A associated with axonal neuropathy,spasticity and autism spectrum disorder

Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A.     

Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot‐Marie‐Tooth disease (CMT4)

Charcot‐Marie‐Tooth disease type 4C (CMT4C) is an autosomal recessive (AR) demyelinating neuropathy associated to SH3TC2 mutations, characterized by early onset, spine deformities, and cranial nerve involvement. We screened 43 CMT4 patients (36 index cases) with AR inheritance, demyelinating nerve conductions, and negative testing for PMP22 duplication, GJB1 and MPZ mutations, for SH3TC2 mutations. Twelve patients (11 index cases) had CMT4C as they carried homozygous or compound heterozygous mutations in SH3TC2. We found six mutations: three nonsense (p.R1109*, p.R954*, p.Q892*), one splice site (c.805+2T>C), one synonymous variant (p.K93K) predicting altered splicing, and one frameshift (p.F491Lfs*32) mutation. The splice site and the frameshift mutations are novel. Mean onset age was 7 years (range: 1–14). Neuropathy was moderate‐to‐severe. Scoliosis was present in 11 patients (severe in 4), and cranial nerve deficits in 9 (hearing loss in 7). Scoliosis and cranial nerve involvement are frequent features of this CMT4 subtype, and their presence should prompt the clinician to look for SH3TC2 gene mutations. In our series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR‐CMT type.