Kothari Sonam

Magnetic resonance imaging correlates of genetically characterized patients with mitochondrial disorders: A study from south India

BACKGROUND Large studies analyzing magnetic resonance imaging correlates in different genotypes of mitochondrial disorders are far and few. This study sought to analyze the pattern of magnetic resonance imaging findings in a cohort of genetically characterized patients with mitochondrial disorders. METHODS The study cohort included 33 patients (age range 18 months-50 years, M:F - 0.9:1) with definite mitochondrial disorders seen over a period of 8 yrs. (2006-2013). Their MR imaging findings were analyzed retrospectively. RESULTS The patients were classified into three groups according to the genotype, Mitochondrial point mutations and deletions (n=21), SURF1 mutations (n=7) and POLG1 (n=5). The major findings included cerebellar atrophy (51.4%), cerebral atrophy (24.2%), signal changes in basal ganglia (45.7%), brainstem (34.2%) & white matter (18.1%) and stroke like lesions (25.7%). Spinal cord imaging showed signal changes in 4/6 patients. Analysis of the special sequences revealed, basal ganglia mineralization (7/22), lactate peak on magnetic resonance spectrometry (10/15), and diffusion restriction (6/22). Follow-up images in six patients showed that the findings are dynamic. Comparison of the magnetic resonance imaging findings in the three groups showed that cerebral atrophy and cerebellar atrophy, cortical signal changes and basal ganglia mineralization were seen mostly in patients with mitochondrial mutation. Brainstem signal changes with or without striatal lesions were characteristically noted in SURF1 group. There was no consistent imaging pattern in POLG1 group. CONCLUSION Magnetic resonance imaging findings in mitochondrial disorders are heterogeneous. Definite differences were noted in the frequency of anatomical involvement in the three groups. Familiarity with the imaging findings in different genotypes of mitochondrial disorders along with careful analysis of the family history, clinical presentation, biochemical findings, histochemical and structural analysis will help the physician for targeted metabolic and genetic testing.

Bilateral hypertrophic olivary nucleus degeneration on magnetic resonance imaging in children with Leigh and Leigh-like syndrome

OBJECTIVE Bilateral hypertrophic olivary degeneration on brain MRI has been reported in a few metabolic, genetic and neurodegenerative disorders, including mitochondrial disorders. In this report, we sought to analyse whether bilateral symmetrical inferior olivary nucleus hypertrophy is specifically associated with mitochondrial disorders in children. METHODS This retrospective study included 125 children (mean age, 7.6 ± 5 years; male:female, 2.6:1) diagnosed with various metabolic and genetic disorders during 2005-2012. The routine MRI sequences (T1 weighted, T2 weighted and fluid-attenuated inversion-recovery sequences) were analysed for the presence of bilateral symmetrical olivary hypertrophy and central tegmental tract or dentate nuclei signal changes. The other imaging findings and the final diagnoses were noted. RESULTS The cohort included patients with Leigh and Leigh-like syndrome (n = 25), other mitochondrial diseases (n = 25), Wilson disease (n = 40), Type 1 glutaric aciduria (n = 14), maple syrup urine disease (n = 13), giant axonal neuropathy (n = 5) and L-2 hydroxy glutaric aciduria (n = 3). Bilateral inferior olivary nucleus hypertrophy was noted in 10 patients, all of whom belonged to the Leigh and Leigh-like syndrome group. CONCLUSION Bilateral hypertrophic olivary degeneration on MRI is relatively often, but not routinely, seen in children with Leigh and Leigh-like syndrome. Early detection of this finding by radiologists and physicians may facilitate targeted metabolic testing in these children. ADVANCES IN KNOWLEDGE This article highlights the occurrence of bilateral hypertrophic olivary nucleus degeneration on MRI in children with Leigh and Leigh-like syndrome, compared with other metabolic disorders.

Clinical and magnetic resonance imaging findings in patients with Leigh syndrome and SURF1 mutations

BACKGROUND Mutation in the SURF1 is one of the most common nuclear mutations associated with Leigh syndrome and cytochrome c oxidase deficiency. This study aims to describe the phenotypic and imaging features in four patients with Leigh syndrome and novel SURF1 mutation. METHODS The study included four patients with Leigh syndrome and SURF1 mutations identified from a cohort of 25 children with Leigh syndrome seen over a period of six years (2006-2012). All the patients underwent a detailed neurological assessment, muscle biopsy, and sequencing of the complete mitochondrial genome and SURF1. RESULTS Three patients had classical presentation of Leigh syndrome. The fourth patient had a later age of onset with ataxia as the presenting manifestation and a stable course. Hypertrichosis, facial dysmorphism and hypopigmentation were the additional phenotypic features noted. On magnetic resonance imaging all patients had brainstem and cerebellar involvement and two had basal ganglia involvement in addition. The bilateral symmetrical hypertrophic olivary degeneration in these patients was striking. The SURF1 analysis identified previously unreported mutations in all the patients. On follow-up three patients expired and one had a stable course. CONCLUSIONS Patients with Leigh syndrome and SURF1 mutation often have skin and hair abnormalities. Bilateral symmetrical hypertrophic olivary degeneration was a consistent finding on magnetic resonance imaging in these patients.

Peripheral neuropathy in genetically characterized patients with mitochondrial disorders: A study from south India.

BACKGROUND There are relatively few studies, which focus on peripheral neuropathy in large cohorts of genetically characterized patients with mitochondrial disorders. This study sought to analyze the pattern of peripheral neuropathy in a cohort of patients with mitochondrial disorders. METHODS The study subjects were derived from a cohort of 52 patients with a genetic diagnosis of mitochondrial disorders seen over a period of 8 years (2006-2013). All patients underwent nerve conduction studies and those patients with abnormalities suggestive of peripheral neuropathy were included in the study. Their phenotypic features, genotype, pattern of peripheral neuropathy and nerve conduction abnormalities were analyzed retrospectively. RESULTS The study cohort included 18 patients (age range: 18 months-50 years, M:F- 1.2:1).The genotype included mitochondrial DNA point mutations (n=11), SURF1 mutations (n=4) and POLG1(n=3). Axonal neuropathy was noted in 12 patients (sensori-motor:n=4; sensory:n=4; motor:n=4) and demyelinating neuropathy in 6. Phenotype-genotype correlations revealed predominant axonal neuropathy in mtDNA point mutations and demyelinating neuropathy in SURF1. Patients with POLG related disorders had both sensory ataxic neuropathy and axonal neuropathy. CONCLUSION A careful analysis of the family history, clinical presentation, biochemical, histochemical and structural analysis may help to bring out the mitochondrial etiology in patients with peripheral neuropathy and may facilitate targeted gene testing. Presence of demyelinating neuropathy in Leighs syndrome may suggest underlying SURF1 mutations. Sensory ataxic neuropathy with other mitochondrial signatures should raise the possibility of POLG related disorder.

The “Double Panda” Sign in Leigh Disease

Although the “face of the giant panda” sign on magnetic resonance imaging (MRI) is traditionally considered to be characteristic of Wilson disease, it has also been reported in other metabolic disorders. This study describes the characteristic “giant panda” sign on MRI in a child with Leigh disease. The diagnosis was based on the history of neurological regression; examination findings of oculomotor abnormalities, hypotonia, and dystonia; raised serum lactate levels; and characteristic brain stem and basal ganglia signal changes on MRI. The midbrain and pontine tegmental signal changes were consistent with the “face of the giant panda and her cub” sign. In addition to Wilson disease, metabolic disorders such as Leigh disease should also be considered in the differential diagnosis of this rare imaging finding.

Mitochondrial Leukoencephalopathies: A Border Zone between Acquired and Inherited White matter Disorders in Children?

BACKGROUND There is emerging evidence implicating mitochondrial dysfunction in the pathogenesis of acquired demyelinating disorders such as multiple sclerosis. On the other hand, some of the primary mitochondrial disorders such as mitochondrial leukoencephalopathies exhibit evidence of neuroinflammation on MRI. The inter-relationship between mitochondrial disorders and episodic CNS inflammation needs exploration because of the therapeutic implications. OBJECTIVE We sought to analyze the clinical course and MRI characteristics in a cohort of patients with mitochondrial leukoencephalopathy to determine features, if any, that mimic primary demyelinating disorders. Therapeutic implications of these findings are discussed. PATIENTS AND METHODS Detailed analysis of the clinical course, magnetic resonance imaging findings and therapeutic response was performed in 14 patients with mitochondrial leukoencephalopathy. The diagnosis was ascertained by clinical features, histopathology, respiratory chain enzyme assays and exome sequencing. RESULTS Fourteen patients [Age at evaluation: 2-7 yrs, M: F-1:1] were included in the study. The genetic findings included variations in NDUFA1 (1); NDUFV1 (4); NDUFS2 (2); LYRM (2);MPV17(1); BOLA3(2); IBA57(2). Clinical Features which mimicked acquired demyelinating disorder included acute onset focal deficits associated with encephalopathy [10/14, 71%], febrile illness preceding the onset [7/14, 50%] unequivocal partial or complete steroid responsiveness [11/11], episodic/ relapsing remitting neurological dysfunction [10/14, 71%] and a subsequent stable rather than a progressive course [12/14, 85%]. MRI characteristics included confluent white matter lesions [14/14, 100%], diffusion restriction [11/14,78.5%], contrast enhancement [13/13,100%], spinal cord involvement [8/13,61.5%], lactate peak on MRS [13/13] and white matter cysts [13/14, 92.8%]. CONCLUSION Clinical presentations of mitochondrial leukoencephalopathy often mimic an acquired demyelinating disorder. The therapeutic implications of these observations require further exploration.

Mitochondrial oxidative phosphorylation disorders in children: Phenotypic, genotypic and biochemical correlations in 85 patients from South India

Mitochondrial oxidative phosphorylation (OXPHOS) disorders account for a variety of neuromuscular disorders in children. In this study mitochondrial respiratory chain enzymes were assayed in muscle tissue in a large cohort of children with varied neuromuscular presentations from June 2011 to December 2013. The biochemical enzyme deficiencies were correlated with the phenotypes, magnetic resonance imaging, histopathology and genetic findings to reach a final diagnosis. There were 85 children (mean age: 6.9±4.7years, M:F:2:1) with respiratory chain enzyme deficiency which included: isolated complex I (n=50, 60%), multiple complexes (n=24, 27%), complex IV (n=8, 9%) and complex III deficiencies (n=3, 4%). The most common neurological findings were ataxia (59%), hypotonia (59%) and involuntary movements (49%). A known mitochondrial syndrome was diagnosed in 27 (29%) and non-syndromic presentations in 57 (71%). Genetic analysis included complete sequencing of mitochondrial genome, SURF1, POLG1&2. It revealed variations in mitochondrial DNA (n=8), SURF1 (n=5), and POLG1 (n=3). This study, the first of its kind from India, highlights the wide range of clinical and imaging phenotypes and genetic heterogeneity in children with mitochondrial oxidative phosphorylation disorders.

Clinical and Neuroimaging Features in Two Children with Mutations in the Mitochondrial ND5 Gene.

Mutations in the mitochondrial-encoded nicotinamide adenine dinucleotide dehydrogenase 5 gene (MT-ND5) has been implicated as an important genetic cause of childhood mitochondrial encephalomyopathies. This study reports the clinical and magnetic resonance imaging findings in two pediatric patients with mutations in the ND5 gene of mitochondrial DNA. The 8-month-old boy with m.13513 G>A mutation presented with infantile basal ganglia stroke syndrome secondary to mineralizing angiopathy. The 7-year-old girl with the m.13514A>G mutation had episodic regression, progressive ataxia, optic atrophy, and hyperactivity. Magnetic resonance imaging of the brain showed bilateral symmetrical signal intensity changes in the thalamus, tectal plate, and inferior olivary nucleus, which subsided on follow-up image. Both the patients had a stable course. Familiarity with the various phenotypic and magnetic resonance imaging findings and the clinical course in childhood mitochondrial encephalomyopathies may help the physician in targeted metabolic-genetic testing and prognostication.

Mitochondrial myopathy, cardiomyopathy, and pontine signal changes in an adult patient with isolated complex II deficiency.

Mitochondrial disorders resulting from an isolated deficiency of complex II of the respiratory chain is rarely reported. The phenotypic spectrum associated with these disorders is heterogeneous and still expanding. This report describes a patient who presented with myopathy, dilated cardiomyopathy, and pontine signal changes on magnetic resonance imaging. Muscle biopsy showed total absence of succinate dehydrogenase on enzyme histochemistry, negative succinate dehydrogenase subunit A (SDHA) activity on immunohistochemistry, and ultrastructural evidence of mitochondrial aggregates of varying sizes confirming the diagnosis of complex II deficiency. A unique phenotype with complex II deficiency is reported.

Palatal Tremor in POLG-Associated Ataxia

Polymerase gamma, the only DNA polymerase in animal cell mitochondria, plays a crucial role in mitochondrial DNA (mtDNA) replication and repair. It consists of two subunits: a p140 catalytic and p55 accessory subunit that are encoded by POLG1 at chromosome locus 15q25 and POLG2 at chromosome locus 17q24.1, respectively. Approximately 250 homozygous and compound heterozygous mutations in POLG1 causing numerous overlapping clinical syndromes have been reported in the last decade and a half. Mutations in POLG2 are emerging as cause of mitochondrial disease that are mainly linked to neuromuscular manifestations. We describe unique clinical and imaging findings in a patient harboring pathogenic mutations in POLG1 and POLG2. A 30-year-old female with intellectual disability presented with progressive dysarthria and ataxia of gait and limbs of seven years duration. She was born to nonconsanguinous parents and there was no significant family history. Examination of cranial nerves revealed normal visual acuity and ocular fundi with bilateral, partial nonfatiguable ptosis and oculomotor abnormalities in the form of slow, hypometric saccades, head thrusting, and saccadic pursuits. Supranuclear vertical up-gaze palsy was noted whereas downgaze was full range (see Video 1). Hearing was normal. Motor system examination showed distal wasting, pes cavus, spasticity of both lower limbs, normal power, and brisk muscle stretch reflexes except ankle jerks, which were absent. Plantar responses were flexor. Sensory system, including touch, pain, joint position, and vibration sense, were within normal limits. Signs of cerebellar dysfunction in the form of cerebellar dysarthria, gaze-evoked nystagmus, and dysmetria, dyssynergia, and intention tremor were noted on finger-nose and knee-heel testing. She had a spastic ataxic gait. She also had facial grimacing, but the striking feature was the presence of palatal tremor (see Video 1). An arrhythmic tremor with frequency ranging from 3 to 10 Hz was recorded from the soft palate (Fig. 1E). Her brain MRI (3.0 Tesla; Philips Achieva, Royal Philips Electronics, Amsterdam, the Netherlands) showed T2/fluid-attenuated inversion recovery hyperintense signals in bilateral thalami, inferior olivary nuclei, and cerebellar white matter (Fig. 1A–D). Muscle biopsy revealed mild subsarcolemmal aggregations of succinic dehydrogenase (SDH) reaction product in a few type I fibers and an occasional cytochrome c oxidase (COX)-deficient fiber. Ragged red fibers were not evident on modified Gomori trichrome (MGT; Fig. 1F–H). Biochemical analysis showed deficiency of multiple respiratory chain complexes. She carried a compound heterozygous mutation at c.3428A.G and c.2243G.C in POLG1 resulting in amino acid change at W748S and E1143G, respectively. In addition, sequencing of POLG2 showed a homozygous mutation in c.1105A.G resulting in R369G amino acid substitution in the polypeptide. Mutations in POLG1, which has a complementary role in mtDNA replication fork, have an established role in mitochondrial disorders. Syndromes with POLG1 include Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy spectrum, myoclonic epilepsy myopathy sensory ataxia, the ataxia neuropathy spectrum, and progressive external ophthalmoplegia. Mutations in POLG2, which encodes the accessory subunit and stimulates the catalytic activity of POLG1 in health, are increasingly recognized and their impact on mitochondrial function are being characterized. Symptoms caused by POLG2 mutations are referable to neuromuscular weakness, such as ptosis, ophthalmoplegia, exercise intolerance, fatigue, muscle pain, hypotonia, and peripheral neuropathy. Other features include failure to thrive, seizures, encephalopathy, respiratory insufficiency, spasticity, gastroesophageal reflux, delayed gastric emptying, and hepatic failure. The salient features in our patient include presence of an arrhythmic palatal tremor and pathogenic mutations in POLG1 and POLG2. Ataxia is a recognized clinical manifestation of