Monday, January 29, 2018

Adult-onset Leigh's syndrome

Jabeen SA, Sandeep G, Mridula KR, Meena AK, Borgohain R, Sundaram C. Adult-onset Leigh's disease: A rare entity. Ann Indian Acad Neurol. 2016 Jan-Mar;19(1):140-2.!po=4.16667

Leigh syndrome (LS) is a heterogeneous familial or sporadic neurodegenerative disorder. It is typically seen in infancy or childhood, although rare cases of adult onset have been described. The authors describe a 37-year-old woman who presented with protracted gastrointestinal symptoms followed by acute brain stem syndrome with severe metabolic acidosis and who subsequently showed dramatic clinical and neuroradiological improvement.

From the article

Adult LD was defined as patients who survived longer than 18 years.   Sakushima et al., extensively reviewed the literature on adult-onset LD and they found that adult LD was rare and its clinical manifestations were different from those of children. They divided the cases into those which fulfilled the Rahman et al., criteria (Rahman's criteria group (RCG)) and those which were diagnosed with the identification of genetic abnormality (laboratory-diagnosed group (LDG)). Adult-onset LD tends to have less incidence of developmental delay, COX deficiency, serum lactate elevation, and basal ganglia lesions. In contrast they have cranial nerve disturbance, pyramidal signs, and cerebellar dysfunction.

A 37-year-old female presented with protracted pain abdomen and vomiting since 3 months; followed by giddiness, headache, and diplopia since 15 days. There was no fever, seizures, limb weakness, or sensory symptoms. Personal and family history was unremarkable. General and other systemic examination was normal. Neurological examination revealed bilateral horizontal gaze palsy with gait ataxia. Rest of the examination was normal. Magnetic resonance imaging (MRI) brain showed dorsal brain stem (midbrain and pons) T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities. In view of recurrent vomiting, clinical and MRI picture, a diagnosis of Wernicke's encephalopathy was made and she was treated with parenteral thiamine. There was marked improvement and she was discharged. Few days later she presented with diplopia, increased swaying while walking, bulbar palsy, breathlessness, and shock. Arterial blood gas (ABG) analysis showed severe metabolic acidosis. Fasting serum lactate was elevated (8 mmol/L; normal: 0.8-2.4 mmol/L). MRI revealed increased brainstem hyperintensities with MR spectroscopy (MRS) of the lesion showing peak lactate.  Cerebrospinal fluid (CSF) lactate was also elevated (4.4 mmol/L; normal: 1.1-2.3 mmol/L). Hemogram and renal and liver function tests were normal. CSF cytology and biochemistry were normal. Further, metabolic work up revealed normal serum copper, ceruloplasmin, and urine copper levels. Serum aquaporin antibodies were negative. A provisional diagnosis of adult-onset LD was considered and patient was treated with mitochondrial cocktail (intravenous thiamine, coenzyme-Q, riboflavin, L-carnitine, and L-arginine) along with ventilator support for respiratory failure. Patient improved dramatically in neurological symptoms and was slowly weaned from the ventilator. Muscle biopsy revealed reduced COX and COX-succinate dehydrogenase (SDH) activity without any evidence of ragged red fibers.  Muscle biopsy was sent to Centre for Cellular and Molecular Biology (CCMB), Hyderabad, India; where muscle deoxyribonucleic acid (DNA) was extracted and sequential analysis for complete mitochondrial genome was done; no pathogenic mutations were observed, however, nuclear part of mitochondrial DNA (mtDNA) of blood was not analyzed. Repeat MRI after 3 months revealed complete disappearance of the hyperintensities. A diagnosis of adult-onset LS was made based on classical radiological appearance, biochemical and histochemical evidence, and excellent response to mitochondrial cocktail. At 1-year follow-up, she was asymptomatic neurologically, but had moderate obstructive sleep apnea with an apnea–hypopnea index of 20/h on overnight polysomnography. Cardiac evaluation which included two-dimensional (2D) echocardiogram, treadmill test, and 24-h Holter monitoring were normal…

The diagnostic criteria by Rahman et al 1996. for LS are as follows:

Progressive neurologic disease with motor and intellectual developmental delay;

Signs and symptoms of brain stem and/or basal ganglia dysfunction;

Elevated lactate levels in the blood and/ or CSF; and

One or more of the following:
     Characteristic features of LS on neuroimaging (symmetric hyperintense lesions in basal
     ganglia or brainstem in T2 sequence),     
     Typical neuropathological changes at postmortem examination, and
     Typical neuropathology in a similarly affected sibling.

The criteria proposed by Sakushima et al., 2011 are:

History of cryptogenic thrive failure or signs of mental retardation, pyramidal signs, cerebellar disturbances, ophthalmoplegia, deafness, dysarthria, or other neurological symptoms are present; and

Bilateral basal ganglia lesions or brainstem lesions with serum or CSF lactate elevation are present (lactate stress test (LST) should be considered when resting lactate levels are normal);

Mitochondrial abnormalities are present in muscle pathology or in biochemical analyses, or known LD gene mutations are present; and

Metabolic disorders, toxins, infection, multiple sclerosis, and Wernicke's encephalopathy can be excluded.

Our patient fulfilled the later criteria as she did not have history of failure to thrive or motor/intellectual delay as required in Rahman et al., criteria. Rather she had recurrent vomiting and brainstem signs…

The major mutations known to occur in LD patients are T8993C, T8993G, T10191C, G13513A, A8344G, and A3243G in mitochondrial genes, and SURF1in the nuclear genome. Currently, there are 24 known mutations in mitochondrial genes and 21 in nuclear genes.  The underlying genetic etiology could not be ascertained in our patient. Recent studies have shown that recognized mtDNA mutations only account for a small proportion of cases of mitochondrial disease.   In addition, nuclear DNA mutations account for a substantial number of mitochondrial disorders which could not be done in our patient due to unavailability. Moreover, mitochondrial respiratory chain analysis in muscle or fibroblasts could not be done in our patient. Adult-onset LD is extremely rare and requires high index of suspicion.

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