Galen N. Breningstall

Carnitine deficiency syndromes

Carnitine deficiency syndromes manifest as metabolic encephalopathy, lipid storage myopathy, or cardiomyopathy. Impairment of long-chain fatty acid metabolism and failure of energy production affect tissues reliant on oxidative metabolism. The accumulation of toxic fatty acyl derivatives impedes gluconeogenesis and urea cycle function which, in turn, causes hypoketotic hypoglycemia, transaminase elevations, and hyperammonemia. Oxidation of accumulated fatty acids through an alternative pathway, omega-oxidation, produces dicarboxylic aciduria. Carnitine must be transported into skeletal muscle. Myopathic carnitine deficiency occurs when this transport mechanism is defective. Most systemic carnitine deficiencies are secondary to other disorders that promote excretion of carnitine as acylcarnitine; however, primary systemic carnitine deficiency, likely due to impaired renal conservation of carnitine, also occurs.

Breath-holding spells

Two particularly common, and frequently frightening, forms of syncope and anoxic seizure in early childhood are pallid and cyanotic breath-holding spells. Pallid breath-holding spells result from exuberant vagally-mediated cardiac inhibition. Cyanotic breath-holding spells are of more complex pathogenesis, involving an interplay among hyperventilation, Valsalva maneuver, expiratory apnea, and intrinsic pulmonary mechanisms. The history is the mainstay of diagnosis; videotape documentation may be possible. Performance of an electrocardiogram to evaluate for prolonged QT syndrome should be strongly considered. In patients with pallid breath-holding spells, a characteristic sequence of changes may be documented on an electroencephalogram with ocular compression, if this study is performed. Spontaneous resolution of breath-holding spell, without sequelae, is anticipated. Reassurance is the mainstay of therapy. Occasionally, pharmacologic intervention may be of benefit.

Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: A new X-linked mental retardation syndrome

Bilateral periventricular nodular heterotopia (BPNH) is a recently recognized malformation of neuronal migration, and perhaps proliferation, in which nodular masses of gray matter line the walls of the lateral ventricles. Most affected individuals have epilepsy and normal intelligence with no other congenital anomalies. A striking skew of the sex ratio has been observed because 31 of 38 probands have been female, and one gene associated with BPNH was recently mapped to chromosome Xq28. We report three unrelated boys with a new multiple congenital anomaly-mental retardation syndrome that consists of BPNH, cerebellar hypoplasia, severe mental retardation, epilepsy, and syndactyly. Variable abnormalities included focal or regional cortical dysplasia, cataracts, and hypospadius. We hypothesize that this syndrome involves the same Xq28 locus as isolated BPNH, and we review the expanding number of syndromes associated with BPNH.

Echocardiographic incidence of cardiac rhabdomyoma in tuberous sclerosis

Cardiac rhabdomyoma occurs frequently in patients with tuberous sclerosis (TS). Although there have been case reports of detection of cardiac rhabdomyoma by 2-dimensional echocardiography, no study has examined the frequency of cardiac rhabdomyoma detected by cardiac ultrasound in patients with TS. Echocardiography was performed in 16 consecutive patients with TS. Physical examination revealed normal cardiac findings in each. Discrete areas of increased acoustic density were found in 8 of the 16 patients (50%). The maximum diameters ranged from 3 to 20 mm. Multiple areas were found in 3 of 8. The left ventricle was involved in 5 of the 8. Six masses were intracavitary and 8 were intramyocardial. No atrial masses were seen. Left ventricular size and function were normal. Although other tumors cannot be excluded, the diagnosis of cardiac rhabdomyoma is almost certain in these young patients with TS. The male predominance and the high incidence of intracavitary and left ventricular masses are similar to those in reported autopsy series, also supporting the diagnosis of cardiac rhabdomyoma. The prognosis and potential for growth of these masses are not known, but can be determined by longitudinal follow-up. Cardiac ultrasound should be considered for all patients with TS regardless of physical findings.

Enzymatic diagnostic test for Muscle-Eye-Brain type congenital muscular dystrophy using commercially available reagents

OBJECTIVES Mutations disrupting the interaction of extra-cellular ligands and alpha-dystroglycan are responsible for an etiologically heterogeneous group of autosomal recessive congenital muscular dystrophies (CMD) that can have associated brain and eye abnormalities. The objective is to develop a diagnostic test for one of these CMDs, Muscle-Eye-Brain disease (MEB), due to mutations in the gene encoding Protein O-Mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). DESIGN AND METHODS POMGnT1 enzyme activity was determined in extracts of muscle biopsies from four MEB patients and various controls using commercially available reagents. RESULTS All four MEB muscle samples showed a highly significant decrease in POMGnT1 activity relative to controls. CONCLUSIONS The assay of POMGnT1 activity in MEB muscle provides a rapid and relatively simple diagnostic test for this disease. CMDs associated with brain malformations such as MEB, WWS and FCMD are heterogenous in clinical presentation and on radiologic examination, suggesting that POMGnT1 assays of muscle biopsies should be used as a screening procedure for MEB in all CMD patients associated with brain malformations.

Cardiac and skeletal myopathy associated with cardiac dysrhythmias

Electrophysiologic studies, echocardiograms, cardiac catheterizations and histologic and biochemical analyses of skeletal muscle biopsies were performed in 10 patients (aged 10 to 37 years, mean 21) who had dysrhythmias as the initial manifestation of cardiomyopathy. Presenting symptoms and signs attributable to dysrhythmias included sudden cardiac arrest in 2 patients, syncope in 3, presyncope in 3 and palpitations in 2. There was no clinical evidence of skeletal muscle weakness in any patient. Multicatheter electrophysiologic evaluation established diagnoses of ventricular tachycardia in 6 patients, primary atrial tachycardia in 2 and third degree infra-Hisian heart block in 1 patient. One patient presenting with palpitations had no inducible arrhythmia or conduction disturbance. Echocardiographic, angiographic and hemodynamic studies demonstrated previously unsuspected dilated cardiomyopathy in 7 patients and restrictive cardiomyopathy in 3. Skeletal muscle histologic characteristics were abnormal in all 10 patients; increases in lipid droplets and endomysial fibrosis were the characteristic findings. Serum free carnitine and short- and long-chain acylcarnitine were normal in 9 patients. However, skeletal muscle long-chain acylcarnitine was reduced in 9 patients. These findings support the concept that in certain patients presenting with dysrhythmias, the dysrhythmia may be a manifestation of cardiac and skeletal (that is, generalized) myopathy.

Hydrosyringomyelia and diastematomyelia detected by MRI in myelomeningocele

Magnetic resonance imaging of the spine in 45 patients with myelomeningocele revealed hydrosyringomyelia in 24 and diastematomyelia in two. No patient at initial imaging manifested symptoms referable to hydrosyringomyelia; both patients with diastematomyelia had flaccid lower extremities. One patient developed an upper extremity monoparesis which resolved with syringo-peritoneal shunt placement; no other patient manifested symptoms or required surgery. Ventriculoperitoneal shunt malfunction produced reversible distention of the syrinx in another patient who remained asymptomatic.

Movement disorders in bacterial meningitis

Movement disorders developed in five children, ages 6 to 21 months, during the course of bacterial meningitis caused by Hemophilus influenzae (one), Streptococcus pneumoniae (one), Neisseria meningitidis (one), or Mycobacterium tuberculosis (two). Athetosis, choreoathetosis, and hemiballismus occurred, ranging in duration from hours to months. Cranial computed tomography, performed in four cases, showed no lesion of the basal ganglia. The movements were of such abrupt onset and severity that in four cases they were initially misinterpreted as seizures, and anticonvulsant therapy was contemplated. It is important to recognize the potential development of movement disorders during the acute phase of bacterial meningitis to preclude the inappropriate administration of anticonvulsant medication.

Siblings with leukoencephalopathy.

Two consanguineous siblings presented with developmental regression and emerging spasticity. Cranial magnetic resonance imaging in both showed diffuse leukoencephalopathy. Further investigation established the siblings as having complex 1 deficiency consequent to a novel homozygous mutation in NDUFV1, a nuclear-encoded subunit of complex 1. Diffuse leukoencephalopathy may be a presentation of complex 1 deficiency.

Massive focal brain swelling as a feature of MELAS

Two patients are reported with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes in whom CT documented massive focal brain swelling with midline shift concurrent with exacerbations of their conditions. Brain swelling producing mass effect should be recognized as a feature of MELAS.