MPV17 Gene Variant Mutation Presenting as Leucoencephalopathy with Peripheral Neuropathy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.333468
Source of Support: None, Conflict of Interest: None
Keywords: Mitochondrial depletion syndromes, MPV17 gene, neuropathy and leukoencephalopathy
Mitochondrial diseases are a clinically heterogeneous group of disorders that can be caused by defects in mitochondrial DNA (mtDNA) or nuclear genes involved in mtDNA genesis and maintenance. The disorders of nuclear genes will have Mendelian inheritance. These disorders due to defects in nuclear genes can be associated with mtDNA deletion syndromes or with the reduction in the mtDNA copy number (mtDNA depletion syndromes, MDS). MDS are autosomal recessive disorders that primarily affect infants or children and are characterized by a severe decrease of mtDNA content leading to organ dysfunction that is likely due to the insufficient synthesis of respiratory chain components. MDS are phenotypically heterogeneous and may affect either a specific organ or a combination of organs, including muscle, liver, brain, and kidney. MPV17, a mitochondrial inner membrane protein required for maintenance of mtDNA, mutations have been though common in children, rarely reported in adult presentation of Neuropathy and Leukoencephalopathy with multiple mtDNA deletions in the muscle., MPV17 mutations are associated with an evolving broader phenotype. We are reporting one such rare case from India with interesting clinical phenotype.
An 18-year-old girl born of second-degree consanguineous parentage with normal birth and development, doing her bachelor course, presented with history of distal weakness of both lower limbs in the form of slipping of footwear without knowledge from both the feet and twisting of ankles while walking, left more than right for six months. These symptoms gradually progressed, and she stopped using footwear for 2-3 months prior to consultation with a neurologist. There was no history suggestive of proximal weakness in lower limbs, UL weakness, sensory, bowel bladder or cognitive disturbances. There was no history of fever, joint pains, dryness of eyes or mouth, recent vaccination, exposure to neuro-toxic drugs. There was no family history of similar illness. On general physical examination, she was thin built, height -163 cm, arm span was 169 cm, had flat feet and hammer toes. There were no thickened nerves. She had no palpable organomegaly.
Neurological examination: Speech and higher mental functions at bedside examination were normal. Her Addenbrooke's III score was 73/100 (cut off point for cognitive decline 82-88/100). She had normal fundi and no cranial nerve deficits. There was distal hypotonia in lower limbs. There was mild wasting of muscles below both knees involving anterior and posterior compartments, more on the left than the right). Muscle power examination showed mild intrinsic muscle weakness in the hands. Ankle dorsi and plantar flexors were grade 2/5. Other muscle groups had normal power. Deep tendon reflexes were brisk except bilateral ankle jerks, that were absent. Sensory examination revealed impaired touch and pinprick in the distal 1/3rd of both the legs and impaired joint position sense in the toes. Romberg's test was positive. There was mild finger nose in-coordination and had bilateral foot drop gait.
Investigations showed mild elevation of ammonia-83; 102; 88 (11-51), lactate-24.7 (4-20), SGOT 45 and SGPT 44 (Upto35); Urine screen for abnormal metabolites was negative, Tandem Mass Spectroscopy, ANA and ANCA profile were negative. Her Serum Cortisol, 24 hrs urinary Aryl sulphatase were normal; Arylsulfatase gene mutation for MLD was negative. Mitochondrial genetic panel for MELAS, MERRF, NARP, LHON, Kearns-Sayre disorders – was negative. Her CSF protein was raised to 160 mgs/ml (upper limit 40 mgs/ml). Her ultrasonography of the abdomen showed altered echotexture of liver. MRI brain showed bilateral symmetrical subcortical and lobar white matter in bilateral supratentorial white matter, with sparing of periventricular white matter and subcortical U fibers bilaterally [Figure 1]. Bilateral cerebellar white matter and posterior column tract in the dorsal brainstem showed T2/FLAIR hyperintensity [Figure 1]. No blooming or diffusion restriction was noted. No contrast enhancement was noted [Figure 2]. Spectroscopy from the involved white matter of centrum semiovale showed presence of inverted lactate peak at 1.3ppm [Figure 3]. Nerve conduction studies were suggestive of distal sensory motor axonopathy in upper and lower limbs. Bilateral visual evoked potentials were normal. Muscle biopsy of left quadriceps showed no ragged red fibres or blue fibres. Left sural nerve biopsy showed severe loss of myelinated fibres with no regenerating clusters. Neuropsychological assessment by neuropsychologist using NIMHANS battery revealed deficits in information processing speed and vigilance. Her verbal fluency and memory were impaired. Her clinical exome genetic testing showed MPV 17 (-) Gene, exon 5, variant c. 293C > T, homozygous mutation which is likely pathogenic. (OMIM Mitochondrial deletion syndrome 6) (These genetic findings were confirmed in two independent Laboratories (MEDGENOME, Bengaluru and CSIR Institute of Genomics, Hyderabad).
Mitochondrial DNA (mtDNA) maintenance defects (mtDNA depletion syndromes, MDS) are a group of diseases caused by the deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics (1). Clinically, MDS are usually classified as one of the three forms: a myopathic form associated with mutations in the thymidine kinase 2 (TK2) gene or the p53-induced ribonucleotide reductase B subunit (RRM2B) gene, an encephalomyopathic form associated with mutations in the ATP-dependant succinyl CoA synthase gene (SUCLA2) or the GTP-dependant succinyl CoA synthase gene (SUCLG1), and a hepatocerebral form associated with mutations in either the Twinkle (PEO1) gene, the polymerase-cA (POLG1) gene, the deoxyguanosine kinase (DGUOK) gene, or with mutations in the MPV17 gene. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. The pathogenic variants in MPV17 were first reported in 2006 by Spinazzola et al. Till date around 100 patients were described in the literature with mutations in the MPV17 gene. MPV17-related hepatocerebral mitochondrial DNA depletion syndrome is frequently seen in the Navajo population of the south-western United States and known as Navajo neurohepatopathy.
MPV17-related mitochondrial DNA (mtDNA) maintenance defect presents with varied clinical manifestations. Two major phenotypes described in the literature were early onset hepato cerebral form (96%) and late onset neuromyopathic form (4%). The age of onset of symptoms in this patient matches the described age for the late onset neuromyopathic form (2-18 years). Our patient has predominantly sensory motor axonal neuropathy with mild cerebellar ataxia. In the case series reported by El-Hattab et al. in 2017, both myopathy and neuropathy were reported. In addition, our patient has sub clinical hepatic involvement in the form of elevated liver enzymes and altered echotexture of the liver in the ultrasonography. A similar phenotype is reported by Blakely et al. in a child from Pakistan in 2012 with a homozygous missense variant (c. 2898C >T; p. Pro98Leu). A novel homozygous p. R41Q mutation in MPV17 reported by Yu-Ri Choi from Korea, causing only axonal sensorimotor polyneuropathy without hepatoencephalopathy.
MRI brain showed symmetrical signal changes in the bilateral cerebral and cerebellar white matter and dorsal brain stem. The exact pathophysiology for selective involvement of some areas is not clear. Similar changes were reported in the literature by Merkle et al., 2012. The most common reported MRI abnormality was diffuse white matter abnormalities resembling leukodystrophy (38%).
There is no established genotype-phenotype correlation with this rare and emerging genetic mutation so far. This MPV 17 exon 5, variant c. 293C > T, homozygous missense mutation was described only in 2 patients. Overall missense mutations were more frequent and thought to have a better prognosis compared to nonsense mutations. The estimate of mitochondrial mitochondria and enzyme assays were not available in this patient, though this is not required for establishing the diagnosis. This could have added additional information.
As per literature, there is no definitive treatment for MPV17-related mitochondrial DNA (mtDNA) maintenance defect. Liver transplantation was tried in early-onset form with variable results. Our patient was advised mitochondrial cocktail and at follow up after 6 months, her symptoms were stabilized. A multidisciplinary symptomatic care, and mitochondrial cocktail may improve the quality of life of these patients.
This is the first case report of MPV17-related mitochondrial DNA (mtDNA) maintenance defect from India as of our knowledge. Mitochondrial DNA depletion syndromes (MDS) are rare mitochondrial disorders with evolving broad genotype and phenotype. This case describes the detailed clinical and imaging findings as well as highlights the importance of genetic testing to make accurate diagnosis.
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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initial will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed
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There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]