Infantile spinal muscular atrophy variant with congenital fractures in a female neonate: evidence for autosomal recessive inheritance

Abstract

H ypertension is one of the most important risk factors for cardiovascular diseases. Despite extensive research examining the causes of blood pressure variation, a significant proportion of blood pressure variation is yet to be explained. Studies of families and twins suggest that 20-40% of blood pressure variation can be attributed to genetic factors.1 Evidence shows that the genetic contribution is even greater for young onset hypertension. 2 We feel that genetic approaches focusing on young onset hypertension will provide new insight into the pathogenesis of hypertension.In our previous report, the affected sib pairs (25 independent, affected sib pairs) method showed positive signs of linkage for markers of the atrial natriuretic peptide gene (NPPA) (D1S1612, p=0.0162), angiotensinogen gene (AGT) (D1S547, p=0.0263), lipoprotein lipase gene (LPL) (D8S1145, p=0.0284), and angiotensin converting enzyme gene (DCP1) (D17S2193, p=0.0256), 3 indicating that multiple pathogenic pathways may be involved in the aetiology of young onset hypertension. Owing to this aetiological complexity, in the current study we focus on high resolution mapping of AGT (located on 1q42-43) and DCP1 (located on 17q23), genes of the renin angiotensin system (RAS). Renin catalyses the first step of the activation pathway of angiotensinogen to angiotensin I, which is then cleaved to angiotensin II by angiotensin I converting enzyme. This cascade can lead to aldosterone release, vasoconstriction, and increased blood pressure. Although the RAS has been extensively studied, it remains unclear how and to what extent RAS gene variants contribute to the blood pressure variations in various human populations. MATERIALS AND METHODSWe have recruited 59 nuclear families (a total of 214 subjects) from a hypertension clinic at Taipei Veterans General Hospital, Taiwan. Our study group included 81 young onset hypertensive patients (59 probands and 22 affected sibs, mean age 30.4 (SD 0.95)), 39 normotensive sibs (mean age 32.2 (SD 1.6)), and 94 parents. Our previous study included 25 affected sib pairs from 18 families for affected sib pair analysis. This transmission disequilibrium test (TDT) study used information from all 59 families with probands. Therefore, the former is a subset of the latter. The protocol of this study was approved by the Human Investigation Committee of the Institute of Biomedical Sciences, Academia Sinica.Polymorphic microsatellite markers located on 1q42-43 and 17q23 were selected based on GeneMap'99 and comprehensive human genetic maps from the Marshfield Medical Research Foundation, and obtained from Multi-Colored Fluorescent Human MapPairs Markers of Research Genetics (Huntsville, AL). Nine markers on 1q42-43 were selected: D1S2805 (245.05 cM), D1S3462 (247.23 cM), D1S459 (247.23 cM), D1S1540 (252.12 cM), D1S235 (254.64 cM), D1S517 (262.96 cM), D1S1149 (262.96 cM), D1S1594 (265.49 cM), and D1S547 (267.51 cM). The six markers on 17q23 were D17S1297 (83.40 cM), D17S1295 (83.40 cM), D17S942 (85.94 cM), ATA108a05 (88.76 cM), D17...

Genetic axonal neuropathies and neuronopathies of pre‐natal and infantile onset

“…Whilst some features of this rare SMA variant are similar to those of X‐linked infantile spinal muscular atrophy, consanguinity in affected kindreds and a female case suggests autosomal‐recessive inheritance ( Borochowitz et al, 1991 ; Courtens et al, 2002 ) . The gene is unknown, and SMN1 and IGHMBP2 mutations are absent ( Felderhoff‐Mueser et al, 2002 ; Van Toorn et al, 2002 ) .…”

“…The antenatal period may be complicated by decreased foetal movement and polyhydramnios ( Borochowitz et al, 1991 ; Felderhoff‐Mueser et al, 2002 ) . Affected infants are severely hypotonic and weak at birth, require respiratory support, and have multiple congenital fractures and osteopenia ( Borochowitz et al, 1991 ; Kelly et al, 1999 ; Courtens et al, 2002 ) . Contractures and foot deformities may also be present, and some patients have generalised oedema ( Borochowitz et al, 1991 ; Courtens et al, 2002 ) .…”

“…Affected infants are severely hypotonic and weak at birth, require respiratory support, and have multiple congenital fractures and osteopenia ( Borochowitz et al, 1991 ; Kelly et al, 1999 ; Courtens et al, 2002 ) . Contractures and foot deformities may also be present, and some patients have generalised oedema ( Borochowitz et al, 1991 ; Courtens et al, 2002 ) . Most die within the first few months of life from respiratory failure.…”

Descriptive Epidemiology of Spinal Muscular Atrophy Type I in Estonia

“…Five of those were male infants and X-linked inheritance could not be excluded in these cases [21][22][23][24] . One was a female who showed no deletion of the SMN1 gene [25] . Our patient with congenital fractures was a female and had exons 7 and 8 of the SMN1 gene deleted.…”

Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

“…Together, these disorders are exceptionally rare, with autosomal recessive or X-linked recessive ( UBA1 ) inheritance and descriptions confined to case reports [34–39]. …”