Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia

Abstract

We identified four unrelated patients (three female, one male) aged 20 to 30 years with hypomyelination, pituitary hypogonadotropic hypogonadism, and hypodontia. Electron microscopy and myelin protein immunohisto-chemistry of sural nerves showed granular debris-lined clefts, expanded abaxonal space, outpocketing with vacuolar disruption, and loss of normal myelin periodicity. Reduced galactocerebroside, sphingomyelin, and GM1-N-acetylglucosamine and increased esterified cholesterol were found. This is a clinically homogeneous progressive hypomyelinating disorder. The term 4H syndrome is suggested.We describe a dysmyelinating leukodystrophy that we characterized using clinical features, neuroimaging, peripheral nerve pathology, and biochemistry. The homogeneous abnormalities of these patients strongly suggest a combination of dysmyelination and a selective pituitary gland endocrine defect. Methods Patient descriptionAll patients had a delay in teeth eruption with hypodontia of the permanent teeth (see details in table). Laboratory testingResults were normal for urinalysis, blood cell count, electrolytes, liver enzymes, cholesterol, triglycerides (elevated in patient 3), amino acids (blood), organic acids (urine), lactate (blood and CSF), CSF protein and glucose levels, blood very-long-chain fatty acids, lysosomal enzymes, and skeletal bone survey. Proteolipid protein gene dosage and sequencing were normal. Karyotype (except patient 3) and screening for SCA 1-3, 6-8, 10, 14, 17 FRDA1, and AOA1 showed no abnormalities. Patient 3 also had familial hypertriglyceridemia, hypercholesterolemia, and balanced chromosomal translocation (46, XX, t(6:14)) that showed no loss of genetic material compared with the unaffected mother and a healthy brother and that was thought to be unrelated to the leukodystrophy.On standard luteinizing hormone (LH)-releasing hormone (RH) stimulation test, no patients had significant LH and follicle-stimulating hormone (FSH) responses, and all patients had normal responses to thyrotropin-releasing hormone and corticotropin-releasing hormone. No other hormonal abnormalities were found.All patients had virtually identical abnormalities on neuroim-aging, suggesting hypomyelination and cerebellar atrophy (figure 1). Magnetic resonance spectroscopy was done only in patient 3, and it showed decreased choline-containing compounds as the only abnormality (not shown). Brainstem auditory responses were normal, but cortical peaks were absent on somatosensory-evoked potentials. Background pattern was continuously slowed with symmetric 6-to 8-Hz activity. EMG and nerve-conduction velocity were normal in all patients.The patients at NIH participated in a research protocol on leukodystrophies. The protocol was approved by the institutional review board of the National Institute of Neurological Disorders and Stroke. All patients or their legal guardians gave their written informed consent, including permission for the nerve biopsies. Nerve biopsyCare was taken by the neurosurgeon to avoid compression, d...

Invited Article: An MRI-based approach to the diagnosis of white matter disorders

“…Systematic MRI pattern rec- ognition is important for research purposes, especially for the definition of novel disorders or description of phenotypic variation. 3,[5][6][7][8][9][10][11][12] For routine practice, the main lines of MRI pattern recognition suffice. They help to establish a reasonably short differential diagnosis.…”

“…In disorders typically associated with peripheral nerve involvement, such as hypomyelination with congenital cataract and hypomyelination with hypodontia and hypogonadotropic hypogonadism (4H syndrome), a peripheral neuropathy is inconstant or may be associated with normal nerve conduction velocity. 10,11,12 Peripheral nerve involvement may occasionally be observed in disorders not typically associated with a peripheral neuropathy, such as Pelizaeus-Merzbacher disease. 24 The DNA repair disorders trichothiodystrophy and Cockayne syndrome are invariably characterized by marked hypersensitivity of the skin to sunlight.…”

“…25 In 4H syndrome, delayed, deficient, and abnormal dentition is an early feature. 11,12 Hypogonadotropic hypogonadism leads to the absence of normal puberty at a later stage. 12 Finally, it should be noted that the cause of hypomyelination presently remains unknown in many patients.…”

“…11,12 Hypogonadotropic hypogonadism leads to the absence of normal puberty at a later stage. 12 Finally, it should be noted that the cause of hypomyelination presently remains unknown in many patients. Hypomyelination constitutes the largest single category among patients with a leukoencephalopathy of unknown origin.…”

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

“…Typically, no gene is identified, but in a small subset of Pelizaeus-Merzbacher-like diseases patients, sequence variations in GJC2 [also known as gap junction protein alpha 12 (GJA12), coding for connexin 46.6 (Uhlenberg et al, 2004;Henneke et al, 2008)], and sequence variations in the gene HSPD1, coding for heat shock 60-kDa protein 1, have been found (Magen et al, 2008). This group also includes syndromes in which hypomyelination is accompanied by other multi-organ involvements such as Cockayne's and trichothiodystrophy syndromes (Weidenheim et al, 2009), and oculodentodigital dysplasia and 4H syndrome (Atrouni et al, 2003;Timmons et al, 2006). (ii) Dysmyelinating disorders with delayed and disturbed myelination, including most amino-acidopathies and organic acidurias.…”