Leigh's disease, also known as sub-acute necrotizing encephalopathy, is a rare progressive metabolic disorder affecting the central nervous system. This disorder is generally seen in infants, and rarely in teenagers and adults. The pathophysiology underlying the disease is a defect in cellular energy production, especially affecting the brain stem. In infants, the earliest sign of this disorder is poor sucking ability, loss of head control, loss of appetite, vomiting, continuous crying, and seizures. The disease progresses rapidly, and infants may also show generalized weakness and lactic acidosis. The latter can even lead to respiratory and renal malfunctioning. Leigh's disease is often associated with movement disorders, most commonly dystonia. Some patients may also show rigidity, tremors, chorea, hypokinesia, myoclonus, or tics. In adults, the sequels include kidney failure and cardiac abnormalities.
A confirmed diagnosis of Leigh's disease is made on the basis of clinical features, biochemical tests, and brain scans. The most common treatment is administration of thiamine. The lactic acidosis can be managed by treating with sodium bicarbonate or citrate. A high-fat low-carbohydrate diet may also help, especially in the case of the X-linked form of the disease. The prognosis for the disease is poor. Even with treatment, most affected infants do not survive past 3-years of age, succumbing to respiratory or cardiac failure. Those with milder forms of the disease may survive up to the teenage years. Worldwide, 1 in 40,000 neonates are born with this disease. However, certain populations, like the one in a particular region in Quebec, Canada, have much higher incidences at 1 in 2,000.
Leigh's disease can be transmitted in several ways. In most affected individuals, the mode of transmission is autosomal, with a vast majority of them due to mutations in the SURF1 gene. The protein product of this gene plays an important part in the assembly of Complex IV of the oxidative phosphorylation pathway. A defect in the gene, therefore, results in disruption of mitochondrial energy production. Mutations in some other nuclear genes involved in the pathway, such as the genes that code for proteins that form part of the pyruvate dehydrogenase complex, also result in Leigh's disease.
In close to a quarter of patients with Leigh's disease, the underlying genetic defect is in one of the mitochondrial genes, and is thus, maternally transmitted. Approximately, 10-20% of patients carry either the m.8993T>G or m.8993T>C mutation in the MT-ATP6 gene. Other mitochondrial genes associated with Leigh's disease include MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and MT-CO3. A rare, X-linked recessive form of Leigh's disease also exists.
Abdul-Rasoul et al. (2001) described the first Kuwaiti family diagnosed with Leigh's disease. This family had three affected boys born to first cousin consanguineous, healthy parents. The first child was diagnosed at the age of 6-months. He presented with developmental delays and frequent bruising. He was found to have poor head control, decreased tone, sustained clonus, persistent metabolic acidosis, and high serum and CSF lactate levels. MRI revealed extensive cerebral atrophy with high signals in the caudate and lentiform nucleus. The acidosis was controlled with sodium bicarbonate and dialysis. The child died within two months of respiratory failure. His younger brother was diagnosed at 3-months of age. He was also found to have persistent metabolic acidosis and high serum and CSF lactate levels. MRI findings were similar to his brother. Muscle biopsy showed fiber atrophy with increased lipids, and deficient cytochrome c oxidase activity. He also died at 7-months of age following progressive cardiorespiratory failure. The youngest child in this family was diagnosed with Leigh's disease at 3-months of age, and he also died at the age of 1.7 years. Autopsy was only performed on the eldest affected brother, in which the brain showed thick leptomeninges, cystic changes in the cerebral hemispheres, and spongiform degeneration. There were three elder boys born to the couple who were completely normal, while another pregnancy ended in an abortion at 4-months gestational age. Abdul-Rasoul et al. (2001) suggested an autosomal recessive pattern of inheritance of the disease in this family.
In a 4-year-old daughter of consanguineous Mauritanian parents, Ogier et al. (1988) described severe muscle cytochrome c oxidase deficiency without clear evidence of clinical muscle abnormality. The child had the de Toni-Fanconi-Debre renal syndrome and acute neurologic deterioration resembling Leigh syndrome. Metabolic studies showed elevated cerebrospinal fluid lactate values contrasting with normal blood lactate, and high 3-hydroxybutyrate/acetoacetate ratio with normal lactate/pyruvate ratio.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Organelle disorders were found in 18 out of 248 diagnosed subjects. Among them, three cases from 2 families suffered pyruvate dehydrogenase deficiency in addition to 7 cases from 6 families who were found to have Leigh disease with undetermined biochemical defects. The estimated incidence of this condition in this cohort was 4 per 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
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