Lewis P. Rowland

Deletions of mitochondrial DNA in Kearns-Sayre syndrome

We have identified large-scale deletions in muscle mitochondrial DNA (mtDN A) in seven of seven patients with Kearns-Sayre syndrome (KSS). We found no detectable deletions in the mtDNA of ten non-KSS patients with other mitochondrial myopathies or encephalomyopathies, or three normal controls. The deletions ranged in size from 2.0 to 7.0 kb, and did not localize to any single region of the mitochondrial genome. The proportion of mutated genomes in each KSS patient ranged from 45% to 75% of total mtDNA. There was no correlation between the size or site of the deletion, biochemical abnormality of mitochondrial enzymes, or clinical severity. The data bolster arguments that KSS is a unique disorder and genetic in origin.

Duchenne muscular dystrophy: Deficiency of dystrophin at the muscle cell surface

Dystrophin is the altered gene product in Duchenne muscular dystrophy (DMD). We used polyclonal antibodies against dystrophin to immunohistochemically localize the protein in human muscle. In normal individuals and in patients with myopathies other than DMD, dystrophin was localized to the sarcolemma of the fibers. The protein was absent or markedly deficient in DMD. The sarcolemmal localization of dystrophin is consistent with other evidence that there are structural and functional abnormalities of muscle surface membranes in DMD.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder

We studied the clinical, biochemical, and genetic features of eight patients with the autosomal recessive mitochondrial syndrome mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). MNGIE is clinically characterized by ophthalmoparesis, peripheral neuropathy, leukoencephalopathy, gastrointestinal symptoms (recurrent nausea, vomiting, or diarrhea) with intestinal dysmotility, and histologically abnormal mitochondria in muscle. Brain MRI scans were consistent with leukodystrophy in seven patients examined. Nerve conduction and EMG studies were compatible with a sensorimotor neuropathy; quantitative EMG of two patients suggested a myogenic process. Muscle mitochondrial enzyme analysis revealed a partial defect of cytochrome c oxidase activity in five patients; three had additional respiratory chain enzyme defects. Two patients had isolated complex I defects, and one had normal respiratory chain function. Southern blot analysis revealed multiple deletions of mitochondrial DNA in four of eight patients.

Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both; peripheral neuropathy; leukoencephalopathy; and mitochondrial abnormalities. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1‐phosphate. We identified 21 probands (35 patients) who fulfilled our clinical criteria for MNGIE. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudo‐obstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26–58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. We have identified 16 TP mutations. Homozygous or compound heterozygous mutations were present in all patients tested. Leukocyte TP activity was reduced drastically in all patients tested, 0.009 ± 0.021 μmol/hr/mg (mean ± SD; n = 16), compared with controls, 0.67 ± 0.21 μmol/hr/mg (n = 19). MNGIE is a recognizable clinical syndrome caused by mutations in thymidine phosphorylase. Severe reduction of TP activity in leukocytes is diagnostic. Altered mitochondrial nucleoside and nucleotide pools may impair mtDNA replication, repair, or both. Ann Neurol 2000;47:792–800

MELAS: An original case and clinical criteria for diagnosis

We describe the full history and postmortem findings in one of the first identified cases of mitochondrial encephalomyopathy with stroke-like episodes (MELAS). To clarify diagnostic criteria, we analyzed 69 reported cases. The syndrome should be suspected by the following three invariant criteria: (1) stroke-like episode before age 40 yr; (2) encephalopathy characterized by seizures, dementia, or both; and (3) lactic acidosis, ragged-red fibers (RRF), or both. The diagnosis may be considered secure if there are also at least two of the following: normal early development, recurrent headache, or recurrent vomiting. There are incomplete syndromes in relatives of patients with the full syndrome and incomplete syndromes might also be encountered in sporadic cases. Some MELAS patients have features of the Kearns-Sayre syndrome (KSS) or myoclonic epilepsy with ragged-red fibers (MERRF), but none had the full KSS syndrome. In partial or confusing cases, analysis of mitochondrial DNA (mtDNA) may point to the correct diagnosis; however, not all patients with clinical MELAS have had the typical mtDNA point mutation and some patients with the mutation have clinical syndromes other than MELAS.

The natural history of primary lateral sclerosis

Objective: To define the syndrome of primary lateral sclerosis (PLS) and disorders that contain features of both ALS and PLS, to determine the time beyond which PLS is less likely to become ALS clinically, and to determine the outcome of people with PLS and those who develop lower motor neuron (LMN) signs. Methods: The authors reviewed the records of all 39 patients initially diagnosed with PLS in 1984 to 2004. Diagnostic subgroups were defined based on clinical features. The authors used Kaplan-Meier methods to estimate the time to diagnosis, linear regression analyses to assess function, and a Cox proportional hazard model to assess survival in subgroups. Results: Of the 39 patients, 29 had only upper motor neuron (UMN) signs on initial evaluation. Thirteen of the 29 were later classified as having UMN-dominant ALS (UMN-D) because they acquired evidence of denervation by EMG (3.17 years) or examination (3.67 years). Sixteen of the 29 patients, classified as clinically pure PLS, retained only UMN signs and a normal EMG (mean follow-up 8.7 years). Ten patients who met criteria for ALS at the initial visit were used as controls. The UMN-dominant ALS group had lower functional scores (p = 0.033) than the PLS group, and similar scores to those with ALS. Survival was longer in both the PLS group (p = 0.027) and the UMN-D group (p = 0.067) than the ALS group. Conclusions: Clinically pure PLS can be defined by isolated UMN signs 4 years after symptom onset, and is a syndrome of slow progression with high levels of function. Prior to the fourth year, the diagnosis of PLS cannot be made with certainty because many patients develop LMN signs. UMN-dominant ALS, defined by predominantly UMN disease with minor LMN signs, has disability similar to ALS, but slower progression.

Premorbid weight, body mass, and varsity athletics in ALS

Several famous athletes have been affected by ALS, and some epidemiologic studies have indicated that vigorous physical activity (heavy labor or athletics) is a risk factor for the disease. In a case-control study of 279 patients with motor neuron diseases and 152 with other neurologic diseases, the authors found that subjects with motor neuron diseases were more likely than controls to report they had always been slim or they had been varsity athletes. For slimness, the odds ratio (OR) was 2.21; 95% CI, 1.40 to 3.47. For varsity athletics, the OR was 1.70; CI, 1.04 to 2.76.

Complications of intravenous immune globulin treatment in neurologic disease

Intravenous immune globulin (IVIg) is advocated as a safe treatment for immune-mediated neurologic disease. We reviewed the medical records of 88 patients who were given IVIg for a neurologic illness. Major complications in four patients (4.5%) included congestive heart failure in a patient with polymyositis, hypotension after a recent myocardial infarction, deep venous thrombosis in a bed-bound patient, and acute renal failure with diabetic nephropathy. Other adverse effects included vasomotor symptoms 26, headache 23, rash 5, leukopenia 4, fever 3, neutropenia 1, proteinuria (1.9 g/day) 1, viral syndrome 1, dyspnea 1, and pruritis 1. Fifty-two patients (59%) had some adverse effect of IVIg infusion, most commonly vasomotor symptoms, headaches, fever, or shortness of breath in 40 (45%), which improved with reduced infusion rate or symptomatic medications. Five (6%) had asymptomatic laboratory abnormalities and seven (8%) had other minor adverse effects. Adverse effects led to discontinuation of therapy in 16% and permanent termination of therapy in 10% of patients. There was no mortality or long-term morbidity. Although adverse effects were frequent, serious complications were rare except in patients with heart disease, renal insufficiency, and bed-bound state. NEUROLOGY 1996;47: 674-677

Guidelines for the Determination of Death: Report of the Medical Consultants on the Diagnosis of Death to the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research

Neurology does not ordinarily reprint articles that have been published in other journals. However, because the American Academy of Neurology Executive Committee has endorsed “Guidelines for the Determination of Death: Report of the Medical Consultants on the Diagnosis of Death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research” and the criteria for the determination of death will be discussed a t the AAN Annual Meeting in Washington, D.C., the article is reprinted here. Editorial comment by Dr. Gaetano Molinari appears on p. 400. Lewis P. Rowland, M.D. Editor-in-Chief, NEUROLOGY

Monoclonal IgM with unique specificity to gangliosides GM1 and GD1b and to lacto‐N ‐tetraose associated with human motor neuron disease

IgM lambda monoclonal antibodies in two patients with motor neuron disease showed the same unique antigenic specificity. They bound to gangliosides GM1 and GD1b and to lacto-N-tetraose-BSA. By immunofluorescence microscopy they bound to central and peripheral nerve tissue and to motor end-plates at the neuromuscular junction. Sera from control subjects did not contain antibodies of similar specificity. Monoclonal IgMs with the same unique specificity could be responsible for motor neuron disease in some patients with monoclonal gammopathies.