Paula and Bobby
Parents of Lillie
Alport syndrome, Autosomal Dominant
What is Alport syndrome, Autosomal Dominant?
Alport syndrome, Autosomal Dominant is a rare disease. It is also known as ATS.
It is still uncertain whether this is a single condition. Heterogeneity is suggested by the strong association with deafness in some families but not in others. The renal lesion in males consists of a progressive degeneration of the glomerular capillary basement membrane, which in the early stages presents as a chronic glomerulo-nephritis with haematuria, and usually ends in renal failure in a large proportion of affected individuals. Recipients of renal transplants can develop anti-GBM antibodies, leading to graft rejection (reviewed by Flinter and Bobrow, 1992). Prosemans et al., (2000) presented preliminary data suggesting that enalapril reduces protein excretion in this condition. Microscopic haematuria is detectable in 80-90% of obligate female carriers. Carrier females may also have anterior lenticonus or macular flecks. Surprisingly, situs inversus may be a feature of the condition. Rezaie-Jami et al., (1996) reported a case and review three other cases from the literature.
Setala et al., (1989) reported a mother and son with apparent Alport syndrome together with macular degeneration, clinically resembling cone dystrophy.
There may be a separate, autosomal dominant, 'Alport-like' syndrome associated with cataracts, and leiomyomatosis of the oesophagus and other organs (eg: the female genital tract) - see Legius et al., (1990) for a review. Leichter et al., (1988) have reported a separate association with achalasia. There is also evidence for an autosomal recessive form of the condition (Feingold et al., 1985; Hasstedt et al., 1986).
Mutations have been demonstrated in the alpha5(IV) collagen gene (COL4A5) at Xq21-q22 (Tryggvason et al., 1993; Knebelmann et al., 1996). This is a component of glomerular basement membrane (GBM). Barker et al., (2001) describe a screening statergy that picks up at least 79% of mutations. King et al., (2002) reported intronic mutations in the COL4A5 gene.
Zhou et al., (1993) detected a new collagen gene, COL4A6, in a head-to-head arrangement with the COL4A5 gene on the X chromosome. Deletion of both genes appeared to give rise to Alport syndrome with benign smooth muscle tumours (leiomyomas). Heidet et al., (1995) provided evidence suggesting that patients with a large deletion involving COL4A6 do not have diffuse oesophageal leiomyomatosis, whereas patients with a truncated COL4A6 gene may have. Ueki et al., (1998) showed that a deletion causing leiomyomatosis eliminated the first coding exon of COL4A5 and the first two coding exons of COL4A6. Garcia-Torres and Orozco (1993) suggest that contiguous gene deletions might also include a gene for congenital cataract.
Mochizuki et al., (1994) demonstrated mutations in the COL4A3 gene in consanguineous pedigrees segregating for the autosomal recessive form of Alport syndrome. Lemmink et al., (1994), in a follow-up paper, studied 22 unrelated patients with sporadic or non-X-linked Alport syndrome and found that 3 patients had mutations. The authors concluded that at least 13% of sporadic Alport cases may have mutations of COL4A3 at 2qter (van der Loop et al., 2000). MPLA analysis improves detection rate(Hertz ewt al., 2008). Mutations in the COL4A4 gene that also maps to this region have been reported in recessive cases (Mochizuki et al., 1994; Boye et al., 1998). Flinter (1997) provides a good review of the clinical and molecular features. Bruttini et al., (2000) provide evidence for mosaicism in the grandparent of a three generation family. Mosaicism was also shown in 1 of 2 male monozygotic twins, discordant for the condition (Matsukura et al., (2004). Mutations in either COL4A4 (82%) or COL4A3 (18%) were found in 17 Chinese autosomal recessive cases (Zhang et al., 2012).
Using next generation exome sequencing, Fallerini et al., (2014) identified autosomal dominant mutations in 31% of their cohort. A family with dominantly inherited Alport and a COL4A3 mutation (Rosado et al., 2015) had some members with late-onset deafness alone.
* This information is courtesy of the L M D.
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What gene changes cause Alport syndrome, Autosomal Dominant?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.
Autosomal Dominant - In the case of autosomal dominant inheritance, just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
X-Linked Dominant - With syndromes inherited in an X-linked dominant pattern, a mutation in just one of the copies of the gene causes the syndrome. This can be in one of the female X chromosomes, and in the one X chromosome males have. Males tend to have more severe symptoms than females.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 104200 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
COL4A3 - 2q36.3
COL4A4 - 2q36.3
MYH9 - 22q12.3
What are the main symptoms of Alport syndrome, Autosomal Dominant?
The typical symptoms of the syndrome are:
Diffuse glomerular basement membrane lamellation, Thickening of the glomerular basement membrane, Progressive, Anterior polar cataract, Azotemia, Myopia, Nephrocalcinosis, Lenticonus, Stage 5 chronic kidney disease, Autosomal dominant inheritance, Proteinuria, Sensorineural hearing impairment, Glomerulonephritis, Hematuria, Hypertension, Hypophosphatemia, Nephrotic syndrome
How does someone get tested for Alport syndrome, Autosomal Dominant?
The initial testing for Alport syndrome, Autosomal Dominant can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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