A Case of Childhood Onset of Extended Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis Phenotype with Pathogenic Polymerase Gamma Variation

Ami Shah; Shilpa Kulkarni; Snehal Mallakmir; Rashid Merchant

doi:10.4103/ipcares.ipcares_2_23

CASE REPORT

Year : 2023 | Volume : 3 | Issue : 2 | Page : 86-89

A Case of Childhood Onset of Extended Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis Phenotype with Pathogenic Polymerase Gamma Variation

Ami Shah, Shilpa Kulkarni, Snehal Mallakmir, Rashid Merchant
Department of Pediatrics, Nanavati Super Specialty Hospital, Mumbai, Maharashtra, India

Date of Submission	02-Jan-2023
Date of Decision	28-Mar-2023
Date of Acceptance	06-Apr-2023
Date of Web Publication	24-May-2023

Correspondence Address:
Dr. Ami Shah
Department of Pediatrics, Nanavati Super Specialty Hospital, Vile Parle West, Mumbai - 400 056, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_2_23

Abstract

Background: Ataxia neuropathy spectrum, including sensory ataxia neuropathy, dysarthria, and ophthalmoparesis (SANDO), is a part of polymerase gamma (POLG) gene-related disorder, a heterogeneous group of mitochondrial disorders. Childhood onset of the SANDO phenotype is rare, and we describe such a case here, probably the first from India. Clinical Description: A 17-year-old girl presented with progressive gait abnormality since 5 years of age, later associated with ptosis and seizures. On examination, she had atrophy of distal small muscles and absent tendon reflexes in addition to ataxia and ptosis. Differentials for a neurodegenerative disorder with cognitive sparing and ophthalmoplegia were suspected. Management: Investigations revealed a mild elevation in serum lactate, transaminases, and creatine phosphokinase, with abnormal neurophysiology showing primary muscle disease with symmetrical sensorimotor polyneuropathy, and a normal neuroimaging. Gene sequencing analysis for the mitochondrial disorder was done, which revealed a pathogenic variation in the POLG gene. The child was kept on supportive management, including antiepileptics. Conclusion: This case shows that the SANDO phenotype of POLG-related disorders, classically seen in adults, may rarely be seen in children. Our case highlights the fact that although many of the progressive neurodegenerative disorders have a nonspecific clinical presentation, biomarkers, and neurophysiologic abnormalities, a few important phenotypic clues and awareness of POLG-related disorders may enable a pediatrician to order focused genetic testing to delineate the etiology.

Keywords: Ataxia, children, gait, mitochondrial disorder, ophthalmoparesis

How to cite this article:
Shah A, Kulkarni S, Mallakmir S, Merchant R. A Case of Childhood Onset of Extended Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis Phenotype with Pathogenic Polymerase Gamma Variation. Indian Pediatr Case Rep 2023;3:86-9

How to cite this URL:
Shah A, Kulkarni S, Mallakmir S, Merchant R. A Case of Childhood Onset of Extended Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis Phenotype with Pathogenic Polymerase Gamma Variation. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Jun 3];3:86-9. Available from: http://www.ipcares.org/text.asp?2023/3/2/86/377510

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is an autosomal recessive systemic disorder, resulting from mitochondrial dysfunction and associated with mtDNA depletion in skeletal muscle and peripheral nerve tissue.^[1] Ataxia neuropathy spectrum (ANS) is now considered a part of a group of conditions called polymerase gamma (POLG)-related disorders.

First described in 2001, pathogenic variations in the POLG gene are now known to cause an overlapping phenotypic spectrum of “POLG-related disorders.”^[2] The umbrella term “POLG-related disorders” were earlier grouped into six clinical syndromes – (1) Alpers–Huttenlocher syndrome (AHS); (2) myocerebrohepatopathy spectrum; (3) myoclonic epilepsy, myopathy, sensory ataxia, including previously described spinocerebellar ataxia with epilepsy; (4) ANS encompassing sensory ataxia, neuropathy, dysarthria, and ophthalmoparesis (SANDO) and mitochondrial recessive ataxia syndrome; (5) autosomal dominant and recessive progressive external ophthalmoplegia (PEO); and (6) mitochondrial neurogastrointestinal encephalopathy.^[3] Advancements in genetic evaluation have now uncovered overlapping and extended phenotypes. These conditions can present at any time from infancy to childhood.

We describe a case of ANS to highlight the phenotypic variability and the need for a combined clinical and genetic approach for diagnosis.

Clinical Description

A 17-year-old girl, born out of nonconsanguineous marriage with normal birth, development, and family history, presented with gait difficulties, drooping eyelids, and recent onset of paroxysmal episodes. Her symptoms started at 5 years of age, with frequent falls and progressive gait difficulty thereafter. Parents noticed drooping of eyelids since 8 years of age, initially presenting only in the evening, but later became persistent. She also showed a change in voice. At 15 years, she developed episodic jerky movements of the limbs in both awake and sleep states, associated with loss of awareness lasting a few seconds, suggestive of myoclonic seizures. Symptoms worsened progressively and had neither diurnal variation nor any trigger. At presentation, she also had fine action tremors with difficulty in swallowing and chewing. The child continued to have normal cognition throughout. The episodic movements were not associated with any limb pain, giddiness, or nausea. She did not have any hearing or respiratory complaint.

On examination, she was alert and able to follow instructions, thin built with weight below the 3^rd centile but normal in height. Her vitals were stable; there was no pallor, clubbing, icterus, lymphadenopathy, or any sign suggestive of any vitamin deficiency. On neurological examination, she had ataxia, ptosis with external ophthalmoplegia, distal muscular atrophy, and fine tremors. Her deep tendon reflexes were absent; however, cranial nerves, muscle power, and posterior column evaluations were normal. Romberg's sign was positive. Examination of other systems was within normal limits. Based on childhood onset, progressive symptoms, and a predominantly neurological involvement with sparing of cognition, a neurodegenerative disorder was suspected. In view of specific eye symptoms, mitochondrial disorders such as Kearns–Sayre and PEO were possible differentials. Inherited neuropathies were also suspected in view of combined proximal and distal muscle involvement.

Management and Outcome

Investigations revealed normal baseline evaluations – hemoglobin 14.2 g/dl, total leukocyte count 10,600/ul (4000–11,000), platelets 2.31 lacs/cumm (1.5–4.5), serum sodium 138 mEq/L (132–144), potassium 4 mEq/L (93.6–4.8), fasting blood sugar 83 mg/dl (70–110), blood urea nitrogen 6.1 (10–15 mg/dl), and creatinine 0.25 mg/dl (0.5–0.9). Her liver enzymes, lactate, and creatine phosphokinase (CPK) were mildly elevated – serum glutamic-oxaloacetic transaminase 85 U/L (0–31), serum glutamate-pyruvate transaminase 46 U/L (0–34), CPK 610 U/l, and lactate 2.8 mmol/l (0.7–2.1). Neurophysiologic studies revealed primary muscle disease with symmetrical sensorimotor polyneuropathy [Figure 1]. The electroencephalogram (EEG) showed slow background with occasional generalized delta bursts and occasional epileptiform discharges. Fundus examination, vision evaluation, audiometry, and neuroimaging of the brain and spine were normal. Deltoid muscle biopsy was also reported as normal. In view of the clinical presentation, abnormal blood, and neurophysiology studies, with clinical presentation, we suspected a mitochondrial disorder; hence, sequencing analysis of nuclear and mitochondrial genome studies was conducted. The mitochondrial genome was negative, but clinical exome by next-generation sequencing revealed a likely pathogenic homozygous missense variant in exon 4 of POLG gene (OMIM* 174763) (chr15: g. 89872286A>C; Depth: ×624; 100% coverage), resulting in the substitution of arginine for leucine at codon 304 (p.Leu304Arg; ENST00000268124.5) [Figure 2]. A diagnosis of POLG-related disorder with SANDO phenotype was made.

Figure 1: Nerve conduction and electromyography studies showing low amplitudes in sensory (a - right sural nerve NCS) and motor nerves (b - right median motor NCS) with negative repetitive nerve stimulation (c - right median nerve RNS) and EMG (d) suggestive of primary muscle disease. This pattern is suggestive of myoneuropathy. NCS: Nerve conduction studies, RNS: Repetitive nerve stimulation, EMG: Electromyography

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Figure 2: An integrated genome browser image showing the pathogenic variation in our child - substitution of 99% of nucleotide A by C in chromosome 15 at 89872286 bp

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The family was counseled regarding the prognosis and the course of her illness. She was started on levetiracetam for her seizures, and in absence of definitive treatment, multivitamins and carnitine supplements were added. Although she remained seizure-free on this, there was minimal improvement in the rest of her symptoms. She was followed up at 4 and 6 months postdischarge, found to have a marginal improvement in her gait and voice, and had become seizure free. However, there was no improvement in her ptosis, and the reflexes persisted to be absent. On telephonic follow-up thereafter, no further improvement was noted, her gait had worsened, and she had breakthrough seizures. Although cognitively normal, she stopped her studies.

Discussion

Childhood-onset progressive ataxia with muscle, speech, and eye involvement may be due to multiple causes which include genetic as well as nongenetic etiologies^[4],[5] [Box 1].

Appropriate history, examination, neuroimaging, and genetic testing help in eliciting the exact diagnosis.

Mitochondrial disorders are one of the leading causes of genetic ataxias with cerebellar, muscle, and ophthalmic involvement. Mitochondrial oxidative phosphorylation disorders, caused by pathogenic variations in mitochondrial or nuclear DNA, lead to an array of pediatric neurological conditions.^[6] Located on chromosome 15q25, the DNA polymerase encoding POLG gene is one of the most common nuclear genes linked to these disorders.^[7] Mitochondrial disorders may be caused by pathogenic variations in either nuclear genes which are involved in its maintenance and functioning or mitochondrial genes. The POLG is a nuclear gene; its variations affect the protein functions that reduce cellular capacity to maintain mitochondria, thus affecting tissues with high-energy demands such as the muscle, liver, and nervous tissue.^[8]

Among the various POLG-related phenotypes, ANS is a rare disorder, and its most common subtype is SANDO, including the triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. The classic type has a young adult onset with sensory neuropathy, followed by ataxia and late-onset dysarthria and ophthalmic involvement.^[1] Other phenotypic presentations include myopathy, seizures, and hearing loss.^[9] The phenotype of our patient was suggestive of this extended SANDO spectrum. Although childhood onset is not reported, adolescent onset has been described.^[10] While ophthalmoplegia also appears early in the disease, epilepsy appears much later.^[8] Peripheral neuropathy can be sensory, motor, mixed, or severe, causing ataxia as seen in this case. Mild muscle involvement is common; however, rare cases of clinical myopathy as described in this report are also known.^[11] This is probably the first case report from India describing the extended SANDO phenotype.

In this disease, serum lactate and CPK may be mildly elevated. The findings of EEG are commonly nonspecific, and neuroimaging is usually normal as seen in our case.^[3] Abnormalities reported in magnetic resonance imaging include white matter abnormalities involving the thalamus, basal ganglia, and cerebellum, and rarely show stroke-like lesions – especially those involving the occipital region, commonly described in MELAS. Liver histopathology and respiratory chain enzyme estimation in muscle biopsy can be diagnostic, but a normal report does not rule out POLG-related disorders.^[3],[11]

Molecular genetic studies are confirmatory for POLG-related disorders. Of the 300 reported pathogenic variations, >95% will be detected by sequence analysis.^[11],[12] Most patients carry homozygous or compound heterozygous variations, but dominant variations have also been reported in a few with PEO phenotype. Three commonly reported pathogenic variations in descending order of prevalence are p. A467T, p. W748S, and the one associated with some of the most pathogenic phenotypes, p. G848S.^[3],[8] The age of onset strongly correlates with the spectrum of symptoms and the severity of the disorder. Infantile-onset disorders like AHS have a more severe course compared to adult-onset PEO, which has a milder phenotype.^[8] Our patient had a known pathogenic L304R homozygous variation, reported to have variable phenotypes, including SANDO.^[8]

Although no specific treatment is available for genetic ataxias, the diagnosis helps in prognosticating and screening of symptomatic, asymptomatic family members as well as counseling for future pregnancies. Sodium valproate and divalproex sodium are contraindicated in this group. Refractory epilepsy may require additional options such as prednisone and a ketogenic diet. The utility of a “mitochondrial cocktail” of vitamins and cofactors is debatable.^[11] Liver transplantation, although reported in varied phenotypes including SANDO, is contraindicated in children with persistent neurological progression.^[3],[11]

Conclusion

The detection of mitochondrial etiology like POLG-related disorders in childhood poses a challenge due to nonspecific symptoms, biomarkers, neurophysiologic testing, and difficulty obtaining histopathological and respiratory chain enzyme analysis. A high degree of suspicion and awareness of such a condition will direct a physician to order sequencing analysis for nuclear and mitochondrial genome and clinical exome, so as to reveal this disorder.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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