Autosomal dominant acute necrotizing encephalopathy.

OBJECTIVE: To define the clinical and biochemical abnormalities of an autosomal dominant form of acute encephalopathy. METHODS: The clinical details of 11 affected family members in comparison with 63 unaffected relatives were analyzed. RESULTS: Affected children become comatose after onset of a febrile illness. Outcomes include full recovery, permanent neurologic impairment, and death. Recurrences produce more severe impairments. Lesions of necrotizing encephalopathy of the thalamus and brainstem are present on autopsy and MRI. Oxidative phosphorylation of intact mitochondria from a muscle biopsy shows loose coupling. Unaffected family members, including obligate carriers, share no clinical characteristics, demonstrating incomplete penetrance. CONCLUSIONS: Characteristic pathology and MRI findings define this disorder of autosomal dominant acute encephalopathy. Leigh syndrome and sporadic acute necrotizing encephalopathy share similarities but are distinct.

New phenotypic variant of adrenoleukodystrophy. Pathologic, ultrastructural, and biochemical study in two brothers.

Adrenoleukodystrophy is not usually considered in the differential diagnosis of the infantile onset of failure to thrive with motor and intellectual retardation. Rather, symptoms have started in childhood and have progressed over some years; not all patients have had overt adrenocortical insufficiency. The two brothers reported here developed symptoms in the neonatal period. In each the nature of the primary cerebral disorder was not recognized, because other etiologic factors clouded the diagnostic studies. In the younger brother, Case 1, a high titer (1:256) for cytomegalovirus (CMV) led to the suspicion that CMV infection accounted for the neurologic and ophthalmologic findings. Progressive neurologic deterioration at the age of 6 years prompted brain biopsy to confirm the diagnosis of progressive CMV encephalitis. In the older brother, Case 2, hemogenic hydrocephalus due to traumatic birth injury was held responsible for the psychomotor retardation and cerebral palsy. At necropsy, the adrenal glands in both cases were severly atrophic. In Case 1, a markedly inflammatory leukodystrophic process affected chiefly the frontal centra semiovalia and internal capsules, with relative sparing of parieto-occipital white matter and subcortical U-fibers. Heavy lymphocyte and monocyte cuffs surrounded many blood vessels in the white matter, and oil-red-O and PAS-positive macrophages were scattered in the zones of myelin disintegration and loss. Focally, the leukodystrophic process was so intense that cavitation necrosis was present, especially in the internal capsules. Further, PAS-positive, striated macrophages were aggregated in large clusters in liver, spleen, and lymph nodes. At the ultrastructural level, linear and gently arced, parallel, coapted or widely separated leaflets measuring 3-4 nm in width were identified in macrophages of the brain biopsy and in autopsy liver and lymph node. Biochemical analysis of fresh, frozen autopsy brain demonstrated cholesterol esters with long-chain fatty acids by thin-layer and gas-liquid chromatography. In Case 2, the leukodystrophic process could be readily identified in the brainstem and cerebellum but was masked in the cerebral hemispheres by the extensive hydrocephalus. The adrenal glands were atrophic and at light microscopy revealed adenomatoid nodules, many ballooned coritcal cells and very rare cells with striated cytoplasm. Masses of PAS-positive macrophages were encountered in liver and lymph nodes. In both cases, only old Wallerian degeneration of the corticospinal tracts was found in the spinal cord.

Reincarnation in cultured muscle of mitochondrial abnormalities. Two patients with epilepsy and lactic acidosis.

Two unrelated 9-year-old boys failed to thrive from ages 5 and 4 years, and had focal cerebral seizures followed by transcent hemipareses. Histochemistry of their muscle biopsies showed "ragged-red" fibers, which ultrastructurally contained clusters of mitochondria having loss of crisp delineation of crista membranes and contained amorphous inclusion material and parallel-packed cristae and sometimes paracrystalline inclusions. In the patients' cultured muscles, similar mitochondrial abnormalities were present. 2,4-Dinitrophenol, introduced to the medium of cultures of normal human muscle, produced mitochondrial abnormalities similar to those of the patients', and the medium of the patients' muscle cultures worsened the mitochondrial abnormalities. This study, in demonstrating a mitochondrial defect reproducible in the cultured muscle fibers and, therefore, intrinsic to the ragged-red muscle fibers themselves, raises the possibility of a collateral mitochondrial defect in CNS cells as part of a multicellular mitochondriopathy.

Carnitine deficiency: clinical, morphological, and biochemical observations in a fatal case.

A fatal case of carnitine deficiency is described. The patient had intermittent metabolic acidosis, fluctuating hepatomegaly, and progressive muscle weakness since 22 months of age. One of two liver biopsies revealed lipid accumulation in the hepatocytes, and a muscle biopsy at age 5 years showed a lipid storage myopathy. Type 1 fibres were the most severely affected. Satellite and vascular endothelial cells also contained abnormal lipid deposits. Quantitative electron microscopy demonstrated an approximately 50-fold increase in lipid material, and a twofold increase in mitochondria in myofibres. The muscle carnitine level was less than one-seventh of the lowest value encountered in 74 biopsies from non-weak or neuromuscular disease controls. The basic abnormality in this patient is assumed to be a defect in carnitine biosynthesis.