Gracile Syndrome

A number sign (#) is used with this entry because GRACILE syndrome is caused by homozygous mutation in the BCS1L gene (603647) on chromosome 2q35.

Clinical Features

Fellman et al. (1998) described a neonatal metabolic disorder characterized by severe intrauterine growth retardation, fulminant lactic acidosis during the first days of life, Fanconi-type amino aciduria, and abnormalities in iron metabolism, including liver hemosiderosis. Affected infants failed to thrive, and they died neonatally or in early infancy. The disease was distinct from other lactic acidoses, neonatal hemochromatosis, and neonatal hepatitis.

Inheritance

Fellman et al. (1998) noted that in Finland 17 patients in 12 families had been diagnosed since 1965. Parents of the patients were healthy, and at least 8 families had 1 or 2 healthy children. The male/female ratio of the patients was 5 to 12. The occurrence of the disease in sibships and in both sexes in families with healthy parents was consistent with autosomal recessive inheritance.

Population Genetics

Because GRACILE syndrome had not been described elsewhere in the world, Fellman et al. (1998) presumed that it represented a new member of the Finnish disease heritage, a group of 30 rare monogenic disorders enriched or encountered only in Finland (Norio et al., 1973; de la Chapelle, 1993). The genealogies of the affected families were traced back to the mid-19th century and the oldest genealogy to the late 17th century, by using church records. Some ancient connections between the families had been established. On the basis of 14 cases diagnosed between 1985 and 1997, the incidence in Finland was estimated to be 1 in 56,000 newborns, with a disease allele frequency of 0.004 and a carrier frequency of 1 in 120. However, the disease is probably underdiagnosed and the true allele frequency may be higher.

Mapping

Visapaa et al. (1998) used the principle of linkage disequilibrium to map the disease locus to 2q33-q37. After an initial localization, conventional linkage analysis was performed in 8 families, with a total of 12 affected infants.

Clinical Management

Fellman et al. (2000) studied whether apotransferrin administration and exchange transfusion could improve outcome in patients with the recessive congenital iron overload disease presenting with intrauterine growth retardation, severe lactic acidosis, amino aciduria, and hemosiderosis of the liver. The serum transferrin concentration was increased to adult levels (2-5 g/L) by intravenous apotransferrin administrations and thereafter exchange transfusion was performed. Two patients were treated. In 1 patient, the transferrin saturation decreased from a baseline value of 100% and remained normal after the third exchange transfusion. In the second patient, a reversible beneficial effect was seen on transferrin saturation and bleomycin-detectable iron. However, both infants died later of the disease, at 10 and 8 weeks of age, respectively.

Molecular Genetics

In Finnish patients with GRACILE syndrome, Visapaa et al. (2002) identified a homozygous mutation in the BCS1L gene that resulted in a ser78-to-gly (S78G; 603647.0005) substitution. They also identified 5 different mutations in the BCS1L gene in 3 British infants, originally reported by Morris et al. (1995), with symptoms resembling those of GRACILE syndrome but with the additional features of complex III deficiency and neurologic symptoms. Visapaa et al. (2002) noted that the Turkish patients with mutations in the BCS1L gene reported by de Lonlay et al. (2001) had a different phenotype; see tubulopathy, encephalopathy, and liver failure due to complex III deficiency (124000).

Nomenclature

Fellman (2001) suggested the acronymic designation GRACILE syndrome for this disorder based on the cardinal clinical findings: growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death.

History

Because the ABCB6 gene (605452) maps to the same region of 2q33-q37 as the GRACILE syndrome and is involved in iron homeostasis, it was considered a highly probable candidate gene for this syndrome (Mitsuhashi et al., 2000; Lill and Kispal, 2001). Visapaa et al. (2002) could find no mutations in the coding region of the ABCB6 gene, and the expression level of ABCB6 in patient fibroblasts was found to be comparable to controls. Haplotype analysis of the critical DNA region provided evidence for positional exclusion also. Based on these data, Visapaa et al. (2002) concluded that ABCB6 is not the causative gene for GRACILE syndrome.