Biomedical subjects
Publications and source records attributed to Y J Crow.
We screened 100 patients with inherited and sporadic lower motor neuron degeneration and identified three novel missense mutations in the glycyl-tRNA synthetase (GARS) gene. One mutation was in the anticodon binding domain and associated with onset in early childhood and predominant involvement of the lower limbs, thus extending the phenotype associated with GARS mutations.
BACKGROUND: Aicardi-Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon alpha metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1). METHODS: A genome-wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families. RESULTS: Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14-21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD-unit support interval. CONCLUSIONS: We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.
Geleophysic dysplasia is an autosomal recessive short-limbed, dysmorphic syndrome. The condition is frequently associated with cardiac valvular disease, which may result in secondary hypertrophy and cardiac failure. We describe two distantly related Pakistani children with classical features of geleophysic dysplasia. Pulmonary stenosis was recognized in both within a few months of birth. The younger child shows no signs of cardiac decompensation at the age of 7 years whilst her older cousin has developed a significant pulmonary gradient requiring surgical intervention in the second decade of life. The natural history of his disorder highlights that the cardiac involvement seen in apparently stable forms of geleophysic dysplasia is frequently progressive.
Genetic syndromes that mimic congenital infection are important to recognize because of the associated risk of recurrence. We describe two brothers born to consanguineous parents with clinical features suggestive of intrauterine infection but with negative serologic investigations. Our observations suggest that Aicardi-Goutieres syndrome (AGS) and pseudo-TORCH syndrome likely represent the same disorder.
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In 1988 we reported two sisters with bilateral Coats' disease, sparse hair, dystrophic nails, and primeval splashes of intracranial calcification. We now provide an update on this family documenting the occurrence of skeletal defects comprising abnormal bone marrow, osteopenia, and sclerosis with a tendency to fractures, a mixed cerebellar and extrapyramidal movement disorder, infrequent epileptic seizures, leukodystrophic changes, and postnatal growth failure. Additionally, we present two previously unreported individuals from Ireland and Switzerland with the identical disorder which we designate Coats' plus. Since our original publication a number of other authors have described, frequently as a "new" syndrome, cases with a variable combination of the same features observed in our patients. We review this literature and suggest that the phenotypic overlap with dyskeratosis congenita may provide a clue to the molecular aetiology of this multisystem disorder.
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Aicardi-Goutiéres syndrome (AGS) is an early onset, progressive encephalopathy characterised by calcification of the basal ganglia, white matter abnormalities, and a chronic cerebrospinal fluid (CSF) lymphocytosis. Cree encephalitis shows phenotypic overlap with AGS although the conditions have been considered distinct because of immunological abnormalities observed in Cree encephalitis. We report that levels of interferon alpha (IFN-alpha), a marker of AGS, are raised in Cree encephalitis. Moreover, linkage analysis indicates that the disorders are allelic and refines the AGS1 locus to a 3.47 cM critical interval. Our data show that a CSF lymphocytosis is not necessary for the diagnosis of AGS and strongly suggest that AGS and pseudo-TORCH syndrome are the same disorder. Recognition of immunological dysfunction as part of the AGS phenotype provides further evidence of a primary pathogenic role for abnormal IFN-alpha production in AGS.
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Primary microcephaly is a genetic disorder in which an affected individual has a head circumference >3 SDs below the age- and sex-related mean. A small but apparently normally formed brain is the reason for the reduced head circumference, and, probably because of this, all affected individuals are mentally retarded. The condition is genetically heterogeneous, and four loci have already been identified. We now report a fifth locus, MCPH5, which is an 8-cM region mapping to chromosome 1q31, defined by the markers GATA135F02 and D1S1678.
We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.
Two distinct clinical subtypes of neuronal ceroid lipofuscinosis caused by mutations in the PPT gene, INCL and vJNCL/GROD, occur at a high frequency in the central region of Scotland. In this paper we summarize the clinical details and the molecular basis underlying the disease in the Scottish patients. Comparison of the combination of mutations in the different clinical types reveals a clear genotype-phenotype correlation.
A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211 , Z max = 2.63, straight theta = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT ; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in vJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.
The Coffin-Lowry syndrome is a rare cause of mental retardation recognised by its distinctive facial and digital features. We have observed an unusual, non-epileptic, cataplexy-like phenomenon in three subjects with the syndrome and we speculate that this feature may go unrecognised. We also provide evidence of neuromuscular dysfunction as part of the phenotype by showing abnormalities on muscle ultrasound in four gene carriers.
Despite improvements in diagnostic techniques and progress made in mapping genes associated with syndromal mental handicap, the estimation of recurrence risks in non-syndromal mental retardation is still dependent on empirical data. Unfortunately, few studies are available to guide the clinician and their results differ significantly. For example, recurrence risks to all sibs of a male index patient with severe mental retardation vary between 3.5% and 14% in commonly quoted series. The present review highlights the problems involved in interpreting the previous work in this area and discusses the definition of mental retardation according to the degree of severity, phenotype, and its pattern of inheritance. In planning future studies, an appreciation of these issues should allow us to derive accurate and comparable risk figures for use in counselling affected subjects and their families.
Cryptic unbalanced chromosome rearrangements in the telomeric bands of human chromosomes constitute a significant cause of "idiopathic" mental retardation. Here, we have described a new strategy based upon comparative genomic hybridisation (CGH) to screen for these abnormalities. A modified CGH analysis showed three unbalanced cryptic rearrangements in five patients from three families. These chromosome abnormalities and their balanced forms in the relatives were then confirmed by fluorescence in situ hybridisation (FISH). This study describes a new approach to the diagnosis of cryptic translocations between the G band negative ends of chromosomes and confirms the significant contribution of cryptic telomeric rearrangements to idiopathic mental retardation.
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We report on 12 children with neuronal ceroid lipofuscinosis (NCL) diagnosed between 1974-1995 in the West of Scotland. Diagnosis was made on the basis of clinical, electrophysiological, radiological and pathological examination including electron microscopy (EM) in all cases. Incidence was calculated on the basis of the year of diagnosis and the live birth rate. Six cases were infantile and 6 juvenile NCL derived from a total of 10 families. No cases of late infantile or early juvenile NCL were identified. All cases were typical in clinical description. Cumulative incidence was 1.61/100,000 live births (0.87 and 0.73/100,000 live births for juvenile and infantile NCL respectively). There was significant delay in diagnosis of the juvenile form of NCL. EM findings were unusual in the juvenile group in that 5 of 6 cases exhibited granular osmiophilic deposits (GROD) rather than typical fingerprint inclusion bodies. Four of these 5 cases also failed to show vacuolation of lymphocytes. Thus, in the West of Scotland, the distribution of NCL cases by type and by EM findings is unusual, and suggests a distinct genetic variant of juvenile NCL, possibly allelic to infantile NCL.