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A 5-year-old boy is brought to your office as a new patient with a complicated history of weakness in his thighs and upper arms with exercise intolerance, recurrent migraine headaches, recurrent vomiting, loss of appetite, and seizures. The symptoms started at the age of 2.5 years. The seizures are described as altered consciousness, with paralysis of one side of his body that progresses to a generalized rhythmic jerking of all 4 extremities. The mother has noted that following his seizures, he experiences some loss of skills without re-attainment of the skills. The seizures had initially occurred every 3 to 4 months, but are now monthly. She has also noted some gradual hearing loss. She reports some polydipsia and polyuria.
His early development was normal, but his development slowed with some periods of regression following the onset of his seizures. In fact, he now seems delayed (at about the level of a 3-year-old) when compared to his peers. He also has problems with attention. His mother has a history of migraines, an unexplained cardiomyopathy, and exercise intolerance. His height and weight are at less than the fifth percentile. Other than myopathic facies, he is nondysmorphic in appearance. No hepatosplenomegaly is noted. His musculature is thin, with noted hypotonia and weakness. His skin is pale.
Laboratory investigations show lactic acidosis both in blood and in the cerebrospinal fluid (> 2.5 mmol) and an elevated lactate-to-pyruvate ratio (> 20 mmol). Cerebrospinal fluid protein was elevated at 80 mg/dL. Brain magnetic resonance imaging shows white matter change in the frontal and parietal white matter, with decreased T1 and increased T2 signal. There is abnormal diffusion within the globus pallidus bilaterally. There is a mild degree of ventriculomegaly, but no obstructive hydrocephalus. There is no intracranial mass lesion (Item Q179).
Of the following, the MOST likely diagnosis is
A. biotinidase deficiency
B. congenital disorder of glycosylation
C. homocystinuria
D. lysosomal storage disease
E. mitochondrial disease
The patient in the vignette has a mitochondrial disorder, most likely MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). He presents with early normal development followed by the development of childhood-onset myopathy, seizures, migraines, early signs of diabetes mellitus, stroke-like episodes associated with periods of regression, laboratory evidence of lactic acidosis in both serum and cerebrospinal fluid (CSF), and elevated CSF protein. In addition, neuroimaging is suggestive of bilateral globus pallidus involvement in the context of progressive white matter changes. This is a classic presentation for MELAS. This patient’s family history of symptoms in his mother also suggests a potential maternal inheritance pattern that is common among mitochondrial disorders arising from mutations in the mitochondrial DNA.
Mitochondrial disorders are a heterogeneous group of diseases arising from functional abnormalities in oxidative phosphorylation, also known as the mitochondrial respiratory chain, which is the final common biochemical pathway for aerobic metabolism. Tissues and organ systems that are extremely dependent on aerobic metabolism are typically involved to the greatest degree, including the heart, muscles, and the nervous system. Mitochondrial disorders can result from gene mutations or deletions in the nuclear DNA or the mitochondrial DNA (mtDNA), thus they can be inherited in an autosomal-recessive, autosomal-dominant, X-linked, or maternal inheritance pattern. Mitochondrial DNA is transmitted exclusively by maternal inheritance, as women give their mitochondrial DNA to all of their offspring and men do not transmit mtDNA to any of their offspring. A woman can transmit a variable amount of mutated mtDNA to each of her offspring, thus yielding significant clinical variability among her children. If a defect is in the nuclear DNA that encodes components of the respiratory chain, it can be transmitted by the mother or father to their offspring in a dominant or recessive pattern.
Mitochondrial disorders can present at any age and may initially affect only a single organ or multiple organ systems; however, the predominant features tend to be neurologic and exhibit myopathic symptoms in most individuals. One of the cardinal features is progressive organ system involvement over the course of the disease. Significant clinical variability is common and presenting symptoms may include short stature, cardiomyopathy, diabetes mellitus, proximal myopathy, intolerance to exercise, pancytopenia, sensorineural deafness, optic atrophy, pigmentary retinopathy, ptosis, and external ophthalmoplegia. Neurologic manifestations are typical and include developmental delay, seizures, dementia, migraine headaches, spasticity, hypotonia, neuropathy, ataxia, encephalopathy, and stroke-like episodes. Many affected patients will manifest a particular cluster of features that will delineate a specific mitochondrial syndrome. Some of the more common syndromes include myoclonic epilepsy with ragged-red fibers, Leigh syndrome, Kearns–Sayre syndrome, MELAS, and chronic progressive external ophthalmoplegia.
Diagnosis is sometimes made by recognizing a characteristic clinical presentation of a specific disorder involving the mitochondria; however, it is frequently necessary to take a good family history, check blood or cerebrospinal fluid (CSF) lactate or pyruvate levels, obtain neuroimaging, order cardiac evaluation, order molecular genetic testing, and obtain a muscle biopsy specimen for histologic evidence, such as ragged red fibers and respiratory chain enzyme analysis, supporting a mitochondrial diagnosis. Neuroimaging findings are diagnostic and may illustrate basal ganglia calcification, diffuse atrophy, focal atrophy of the cortex or cerebellum, generalized leukoencephalopathy (white matter changes), or cerebellar atrophy. Laboratory findings commonly feature lactic acidosis in the blood or CSF.
Treatment of mitochondrial disorders is mainly supportive from a systemic standpoint because there is no defined cure at this time. Certain mitochondrial disorders can benefit from supplementation of vitamins and cofactors, such as coenzyme Q10, riboflavin, idebenone, or carnitine depending on the disorder, but a systematic review of the Cochrane database finds no evidence of the global benefit of these supplements for mitochondrial disorders.
Biotinidase deficiency, if untreated, presents with seizures, hypotonia, developmental delay, vision abnormalities, hearing loss, ataxia, hair loss, and skin rashes in young children. As the children age, they develop spastic paresis and motor weakness. It is commonly diagnosed on newborn screening because it is a highly treatable disorder that is amenable to oral supplementation of biotin with excellent outcomes. Once many of the manifestations described have occurred, they are typically irreversible; thus the importance of early recognition and treatment.
Congenital disorders of glycosylation are a group of disorders caused by altered glycosylation of N-linked oligosaccharides. These disorders present in infancy with clinical variability, ranging from severe developmental delay, hypotonia, and systemic involvement to coagulopathy with stroke-like episodes, to normal development with associated recurrent hypoglycemia and failure to thrive. Patients often have inverted nipples, abnormal subcutaneous fat distribution, strabismus, gastroesophageal reflux, hypoproteinemia because of protein-losing enteropathy, and a hypoplastic cerebellum with ataxia. It is diagnosed with a carbohydrate-deficient transferrin isoform analysis, which is a biochemical screening test.
Homocystinuria patients have a “marfanoid” appearance. This disorder is caused by cystathionine β-synthase deficiency resulting in intellectual delays, ectopia lentis, severe myopia, tall stature, and thromboembolism that can lead to an early death. Biochemical features include significantly elevated concentrations of plasma homocystine, total homocysteine, and methionine. Treatment is focused on correction of the biochemical abnormalities involving plasma homocystine and homocysteine concentrations that can help prevent thrombosis. Patients are typically placed on protein- and methionine-restricted diets, as well as betaine, folate, and vitamin B12 supplementation.
Lysosomal storage disorders are a heterogeneous group of disorders that present with accumulation of undigested or partially digested macromolecules in varying organs, causing cellular dysfunction and systemic pathology. They are classified by the type of the accumulated substrate: mucopolysaccharidoses, mucolipidoses, oligosaccharidoses, etc. Patients can present with coarse facies, macroglossia, dysostosis multiplex, cardiomegaly, hepatosplenomegaly, unusual ophthalmologic findings (corneal clouding, cherry-red spot in the macula), developmental delay, regression, hypotonia, seizures, and intellectual disability.