Canavan Disease ; chemically induced ; complications ; Hearing Loss, Sudden ; etiology ; Heroin ; poisoning ; Humans ; Male ; Middle Aged

OBJECTIVE: To explore the genetic basis for a Chinese patient suspected for Canavan disease. METHODS: Whole exome sequencing (WES) was carried out for the proband, and candidate variants were verified by Sanger sequencing of the proband, her parents and brother. Prenatal diagnosis was provided to her mother by chorionic villi sampling (CVS) upon her subsequent pregnancy. RESULTS: The proband, a 4-month-old female infant, had manifested drowsiness, hypotonia and apathy. Urine metabolism screening showed elevated N-acetylaspartic acid. Cranial magnetic resonance imaging revealed abnormal myelination and multiple abnormal signals in large brain areas. WES revealed that the proband has harbored compound heterozygous variants of the ASPA gene, namely c.187A>G (p.Arg63Gly) in exon 1 and c.634+1G>A (P.?) in exon 4. Sanger sequencing confirmed that the c.187A>G (p.Arg63Gly) and c.634+1G>A (p.?) variants were respectively inherited from her mother and father. Her phenotypically normal brother has carried a heterozygous c.634+1G>A (p.?) variant. Prenatal diagnosis by CVS indicated that the fetus was a heterozygous carrier of the c.187A>G variant. CONCLUSION WES can facilitate the diagnosis of Canavan disease, particularly for those lacking specific phenotypes of the disease. The compound heterozygous variants of the ASPA gene probably underlay the Canavan disease in this patient, and the result has enabled prenatal diagnosis for this family.
Canavan Disease/genetics* ; China ; Female ; Humans ; Male ; Mutation ; Pedigree ; Pregnancy ; Prenatal Diagnosis

Canavan disease, also known as van Bogaert-Bertrand disease, is a rare autosomal recessive disorder characterized by early an onset and a progressive spongyform degeneration of the brain, associated with an edema of the central nerve system, intramyelinic swelling and neurologic symptoms. This disorder is most prevalent in people of Ashkenazi Jewish descent but has been observed in other ethnic groups. Patients have severe mental retardation, poor head control, macrocephaly and seizures. Canavan disease is caused by the accumulation of N-acetylaspartic acid(NAA) in the brain as the result of a deficiency of aspartoacylase(ASPA) activity. Most children are reported to have the infantile form, becoming symptomatic between three and six month of age, after unremarkable prenatal and perinatal course. We experienced a case of Canavan disease in a six day old female newborn baby, associated with seizure, degeneration of brain white matter and markedly elevated urine N-acetylaspartic acid(NAA) level. So, we report the case with a brief review of the related literature.
Brain ; Canavan Disease* ; Child ; Edema ; Ethnic Groups ; Female ; Head ; Humans ; Infant, Newborn ; Intellectual Disability ; Macrocephaly ; Neurologic Manifestations ; Seizures

Canavan disease(CD) is a rare autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase and the accumulation in brain of N-acetylaspartate(NAA). CD has been reported mainly Ashkenazi Jews but also occurs in other ethnic groups. Usually it presents as early as the third month of life with megalencephaly, hypotonia later progressing to hypertonia, psychomotor and mental retardation, blindness, occasionally deafness and seizure. Diagnosis is based on the clinical feature, N-acetylaspartic aciduria, radiologic and pathologic findings. Histologically, the affected white matter shows extensive vacuolation and demyelination. There is no treatment for CD and the only prevention is through genetic counselling and prenatal diagnosis. We experienced a case of Canavan disease that was presented with hypotonia and developmental delay. Diagnosis was confirmed histologically. Radiologic findings are extensive high signal throughout the white matter on T2-weighted MRI and increased NAA peak and decreased choline peak of the white matter on MR spectroscopy.
Blindness ; Brain ; Canavan Disease* ; Choline ; Deafness ; Demyelinating Diseases ; Diagnosis ; Ethnic Groups ; Humans ; Intellectual Disability ; Jews ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Muscle Hypotonia ; Prenatal Diagnosis ; Seizures

OBJECTIVETo investigate the relationship between heroin spongiform leucoencephalopathy and respiratory chain complex I deficiency.

METHODSThe activity of respiratory chain complex I in peripheral white blood cell mitochondria was compared between 36 cases of heroin spongiform leucoencephalopathy and 36 healthy subjects using enzyme-linked immunosorbent assay (ELISA).

RESULTSThe activity of respiratory chain complex I was 5.6∓2.4 U/ml in patients with heroin spongiform leucoencephalopathy, significantly higher than that in the normal subjects (4.2∓2.1 U/ml, t=2.634, P<0.05).

CONCLUSIONIn patients with heroin spongiform leucoencephalopathy, mitochondrial dysfunction results in energy metabolism disorder to cause extensive demyelination of the cerebral white matter. Respiratory chain complex I deficiency of the mitochondria plays a significant role in the pathogenesis of heroin spongiform leucoencephalopathy.

Adult ; Canavan Disease ; etiology ; metabolism ; pathology ; Case-Control Studies ; Electron Transport ; Female ; Heroin Dependence ; complications ; metabolism ; pathology ; Humans ; Male ; Middle Aged ; Mitochondrial Diseases ; metabolism ; Young Adult

PURPOSE: Leukodystrophies have been defined as inherited metabolic disorders of myelin resulting in abnormal development or progressive destruction of the white matter. This study was performed to investigate the clinical manifestations and treatments of leukodystrophies in a single Korean tertiary center. METHODS: We retrospectively analysed the medical records of patients who had been diagnosed with leukodystrophy from May 1995 to May 2010 at the Asan Medical Center. RESULTS: During the 15-year study period, 36 cases of leukodystrophies were diagnosed with an verage age at symptom presentation of 49 months. Prominent symptoms at presentation were developmental delay (41%) and seizure (25%); however, nystagmus, developmental regression, hearing loss, gait disturbance, visual disturbance, attention deficit, hypotonia, hyperpigmentation, and hemiparesis were also observed. On MRI, periventricular involvement was noted frequently. The most common diagnoses were adrenoleukodystophy (25%), metachromatic leukodystrophy (11%), Krabbe disease (11%), and Pelizaeus-Merzbacher disease (8.3%). No final diagnosis was made in 14 cases (41%). Bone marrow transplantation was performed in 4 patients and showed favorable prognoses. CONCLUSION: Clinical features of leukodystrophies are not specific to diagnosis and most leukodystrophies remain undiagnosed; however, a logical algorithm based on prevalence could aid the laboratory testing. Because early detection and diagnosis is crucial for treatment and prognosis, it is important to have a high index of suspicion and watchful screening of familial history.
Adrenoleukodystrophy ; Bone Marrow Transplantation ; Canavan Disease ; European Continental Ancestry Group ; Gait ; Hearing Loss ; Humans ; Hyperpigmentation ; Leukodystrophy, Globoid Cell ; Leukodystrophy, Metachromatic ; Logic ; Mass Screening ; Medical Records ; Muscle Hypotonia ; Myelin Sheath ; Paresis ; Pelizaeus-Merzbacher Disease ; Prevalence ; Prognosis ; Retrospective Studies ; Seizures

OBJECTIVETo elucidate the relation between cytochrome P4502D6 (CYP2D6) gene polymorphism and the susceptibility of heroin spongiform leucoencephalopathy (HSLE).

METHODSWith polymerase chain reaction-restriction fragment length polymorphism technique, the cytochrome P4502D6 gene polymorphisms were analyzed in HSLE cases and control subjects.

RESULTSThe frequencies of CYP2D6 (CYP2D6/C188, CYP2D6/L2938, CYP2D6/G4268) gene mutations were higher in HSLE patients than in the controls.

CONCLUSIONThe CYP2D6 gene mutation is associated with a high risk of HSLE.

Adult ; Canavan Disease ; chemically induced ; genetics ; Cytochrome P-450 CYP2D6 ; genetics ; Female ; Heroin ; adverse effects ; Heroin Dependence ; complications ; Humans ; Male ; Middle Aged ; Mutation ; Polymorphism, Restriction Fragment Length ; Young Adult

OBJECTIVETo investigate the pathological characteristics of heroin spongiform leukoencephalopathy (HSLE).

METHODSCerebral tissue specimens were obtained from 15 patients with HSLE and the histological observations under optical and electron microscopes were carried out by HE, Bielschowsky's, and chromotrope 2R-brilliant green staining.

RESULTSHSLE was characterized primarily by spongiform vacuolar degeneration of the cerebral white matter. Neurons in the gray matter, Purkinje and granular cells in the cerebella remain intact in all the cases. Numerous vacuoles, which merged to form larger cavities, appeared in the damaged white matter, and the axons survived in the deep white matter. The myelin sheath in the cerebellar white matter sustained more severe damages than those in the cerebral white matter. No vacuoles or lymphocyte infiltration occurred in the small peripheral vessels.

CONCLUSIONHSLE is pathologically characterized by vacuolar degeneration due to primary damage of the myelin, and the spongiform vacuolar degeneration is closely associated with the severity of demyelination in the white matter.

Adult ; Autopsy ; Canavan Disease ; etiology ; pathology ; Cerebellum ; chemistry ; pathology ; ultrastructure ; Cerebral Cortex ; chemistry ; pathology ; ultrastructure ; Female ; Heroin Dependence ; complications ; Humans ; Male ; Microscopy, Electron ; Middle Aged ; Neurons ; chemistry ; pathology ; Purkinje Cells ; chemistry ; pathology ; Staining and Labeling ; methods ; Young Adult