Alternative titles; symbols
SNOMEDCT: 111303009; ORPHA: 816; DO: 14501;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p11.2 | Sjogren-Larsson syndrome | 270200 | Autosomal recessive | 3 | ALDH3A2 | 609523 |
A number sign (#) is used with this entry because Sjogren-Larsson syndrome (SLS) is caused by homozygous or compound heterozygous mutation in the ALDH3A2 gene (609523), which encodes fatty aldehyde dehydrogenase (FALDH), on chromosome 17p11.
Sjogren-Larsson syndrome (SLS) is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, impaired intellectual development, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (summary by Lossos et al., 2006).
The skin changes in Sjogren-Larsson syndrome are similar to those of congenital ichthyosiform erythroderma (242100), although considerable variations in severity have been described (Goldsmith et al., 1971). Link and Roldan (1958) reported cases. Blumel et al. (1958) referred to the neurologic disorder as spastic quadriplegia. Sjogren (1956) and Sjogren and Larsson (1957) suggested that all of their 28 cases were derived from the same mutation, which occurred about 600 years ago, and that about 1.3% of the population of northern Sweden is heterozygous for the gene. About half the cases have pigmentary degeneration of the retina. Lesions of the ocular fundus were discussed by Gilbert et al. (1968). Retinal glistening white dots are characteristic. Ecchymoses are present at birth or soon after. Most of the patients never walk. Stature tends to be short. About half the patients have seizures. Clinical improvement occurs with fat restriction and supplementation with medium chain triglycerides.
Rayner et al. (1978) described 2 brothers and a sister with a syndrome combining many of the features of the Sjogren-Larsson syndrome but possibly distinct. They reviewed the group of disorders sharing phenotypic features with the Sjogren-Larsson syndrome. This Sjogren syndrome is sometimes called the T. Sjogren syndrome to distinguish it from the sicca syndrome (see 200400, 270150), which was described by Henrick Sjogren, Swedish ophthalmologist born in 1899.
Jagell and Liden (1982) studied all 36 SLS patients alive in Sweden in 1980. Slight or moderate hyperkeratosis, less pronounced on the face, was already present at birth, but collodion membranes were never seen. Ichthyosis developed to its full extent during infancy. The skin changes were concentrated on the neck and lower abdomen and in the flexures, where the scales were often dark. Hair and nails and ability to sweat were unaffected. Glistening spots in the ocular fundus were an obligatory and early sign in all 30 examined Swedish patients with Sjogren-Larsson syndrome (Jagell et al., 1980).
In northern Norway, Gedde-Dahl et al. (1984) encountered a family in which 3 sibs had a form of ichthyosis very similar to that of the Sjogren-Larsson syndrome but with none of the associated neurologic features; see 270220.
Willemsen et al. (2000) studied 15 patients with Sjogren-Larsson syndrome with proven fatty aldehyde dehydrogenase deficiency and found that all had juvenile macular dystrophy of the retina. The patients exhibited highly characteristic bilateral, glistening yellow-white retinal dots from the age of 1 to 2 years onward. The number of dots increased with age. The extent of the macular abnormality did not correlate with the severity of the ichthyosis or with the severity of the neurologic abnormalities. A high percentage of patients showed additional ocular signs and symptoms, notably marked photophobia.
Cultured skin fibroblasts from SLS patients show impaired hexadecanol oxidation due to deficiency of fatty alcohol: NAD+ oxidoreductase. The deficiency in patients and heterozygotes can also be detected by studying leukocytes (Rizzo et al., 1987). Rizzo et al. (1988) studied lipid metabolism in cultured skin fibroblasts. Intact SLS fibroblasts incubated in the presence of labeled palmitate accumulated more radioactive hexadecanol than did normal cells, whereas incorporation of radioactivity into other cellular lipids was unaltered. The hexadecanol content of SLS fibroblasts was abnormally elevated. Rizzo et al. (1988) showed that fatty alcohol:NAD+ oxidoreductase, the enzyme catalyzing the oxidation of hexadecanol to fatty acid, was deficient in SLS fibroblasts. Mean activity was 13% of that in normal fibroblasts. Fibroblasts from 2 obligate heterozygotes had intermediate levels of enzyme activity. In a later report, Rizzo et al. (1989) described studies of fatty alcohol metabolism in 8 patients and 9 obligate heterozygotes.
Lossos et al. (2006) reported follow-up on 6 sibs with SLS from a consanguineous Arab family previously reported by Rogers et al. (1995). The sibs ranged in age from 16 to 36 years. They all exhibited typical features of the disorder but severity with no apparent age correlation. Although there was some evidence for progression of macular degeneration, cutaneous and neurologic features were not progressive. Cerebral magnetic resonance spectroscopy (MRS) showed a decrease in the 1.3-ppm lipid peak among the older sibs, suggesting reduced disease activity. Lossos et al. (2006) suggested the presence of compensatory factors to explain the clinical variability among sibs with the same mutation.
Jack et al. (2015) characterized the retinal findings in 9 patients, ranging in age from 3 to 23 years, with SLS and ALDH3A2 mutations. All 9 exhibited generalized ichthyosis, spastic diplegia, photophobia, ichthyosis of the upper eyelid skin, and glistening macular crystals. Optical coherence tomography in 14 eyes of 7 patients showed that macular crystals were present in all layers, but predominantly in the inner nuclear and outer plexiform layers. Full retinal thickness was reduced by 22%, the inner nuclear layer was reduced by 30%, and the outer nuclear layer was reduced by 40%. Fundus autofluorescence (FAF) and fluorescein angiography (FA) showed retinal pigment epithelium atrophy. All 4 patients imaged with FAF showed heterogeneous macular autofluorescence with crystals. All 4 eyes evaluated with FA had window defects and crystals without the presence of leakage or an enlarged foveal avascular zone.
Fatty alcohol:NAD+ oxidoreductase is a complex enzyme that consists of 2 separate proteins that sequentially catalyze the oxidation of fatty alcohol to fatty aldehyde and then to fatty acid. In studies designed to determine whether the biochemical defect in SLS lies in the former step, fatty alcohol dehydrogenase (FADH), or the latter step, fatty aldehyde dehydrogenase (FALDH), Rizzo and Craft (1991) showed that FALDH is selectively deficient and FADH normal. The extent of FALDH deficiency in SLS cells depended on the aliphatic aldehyde used as substrate. FALDH activity in obligate SLS heterozygotes was approximately 50% of the mean normal activity when octadecanal was used as substrate.
In Sweden, Jagell et al. (1981) traced 58 patients in 41 families, of whom 35 were alive. Of the 58, 45 were born in a restricted area in the northeast of Sweden. The prevalence of the disorder, the frequency of heterozygotes, and the gene frequency in the county of Vasterbotten were estimated as 8.3 per 100,000 persons, 2.0%, and 0.01, respectively.
Based on linkage analysis and allelic association, Pigg et al. (1994) mapped the SLS gene to chromosome 17. Meiotic recombinations suggested that the gene is flanked by D17S805 on the centromeric and D17S783, D17S959, D17S842, and D17S925 on the telomeric side. Strong allelic association to D17S805 suggested that the mutation is located close to this marker. Haplotype analysis was consistent with founder effect, which had previously been suggested by genealogic evidence. In 7 pedigrees of diverse ethnic origins, Rogers et al. (1995) confirmed the linkage of SLS to the pericentric region of chromosome 17. Patients from 2 consanguineous Egyptian families were homozygous at all 9 marker loci in this region, suggesting that in these patients the region of chromosome 17 carrying the SLS gene is identical by descent. The authors had also identified several YACs that contained both the FALDH gene and the D17S805 marker that is closely linked to SLS. They concluded that FALDH may be part of the cluster of aldehyde dehydrogenase genes on proximal 17p as an aldehyde dehydrogenase gene (ALDH3; 100660), which maps to 17p11.2, was found to colocalize with the FALDH gene and D17S805 on 2 YACs. Rogers et al. (1995) found linkage of the SLS locus to 17p in families of Arab, mixed European, Native American, and Swedish descent, thereby providing evidence for genetic homogeneity.
The transmission pattern of SLS in the families reported by De Laurenzi et al. (1996) was consistent with autosomal recessive inheritance.
By sequence analysis of the FALDH gene from 3 unrelated SLS patients, De Laurenzi et al. (1996) identified biallelic mutations (609523.0001-609523.0004).
In patients from northern Sweden with SLS, Sillen et al. (1997) identified a homozygous missense mutation in the FALDH gene (609523.0005).
Sillen et al. (1998) reported studies of 16 SLS families from Europe and the Middle East, which resulted in the identification of 11 different mutations in the ALDH3A2 gene. The spectrum of mutations characterized in their study included 5 nucleotide substitutions resulting in amino acid changes, 5 frameshift mutations introducing a stop codon, and 1 in-frame deletion with insertion at the same position. Polymorphisms were also identified. The mutations were widely distributed throughout the gene.
Blumel, J., Watkins, M., Eggers, G. W. N. Spastic quadriplegia combined with congenital ichthyosiform erythroderma and oligophrenia. Am. J. Dis. Child. 96: 724-726, 1958. [PubMed: 13594021] [Full Text: https://doi.org/10.1001/archpedi.1958.02060060726013]
De Laurenzi, V., Rogers, G. R., Hamrock, D. J., Marekov, L. N., Steinert, P. M., Compton, J. G., Markova, N., Rizzo, W. B. Sjogren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nature Genet. 12: 52-57, 1996. [PubMed: 8528251] [Full Text: https://doi.org/10.1038/ng0196-52]
Gedde-Dahl, T., Jr., Rajka, G., Larsen, T. E., Jellum, E. Autosomal recessive ichthyosis in Norway: II. Sjogren-Larsson-like ichthyosis without CNS or eye involvement. Clin. Genet. 26: 242-244, 1984. Note: Paper presented at the Third Nordic Conference of Medical Genetics.
Gilbert, W. R., Jr., Smith, J. L., Nyhan, W. L. The Sjogren-Larsson syndrome. Arch. Ophthal. 80: 308-316, 1968. [PubMed: 5302287] [Full Text: https://doi.org/10.1001/archopht.1968.00980050310003]
Goldsmith, L. A., Baden, H. P., Canty, T. G. Sjogren-Larsson syndrome. Acta Derm. Venereol. 51: 374-378, 1971. [PubMed: 4109276]
Gustavson, K. H., Jagell, S. Dermatoglyphic patterns in the Sjogren-Larsson syndrome. Clin. Genet. 17: 120-124, 1980. [PubMed: 7363498] [Full Text: https://doi.org/10.1111/j.1399-0004.1980.tb00119.x]
Heijer, A., Reed, W. B. Sjogren-Larsson syndrome: congenital ichthyosis, spastic paralysis, and oligophrenia. Arch. Derm. 92: 545-552, 1965. [PubMed: 5844397] [Full Text: https://doi.org/10.1001/archderm.92.5.545]
Jack, L. S., Benson, C., Sadiq, M. A., Rizzo, W. B., Margalit, E. Segmentation of retinal layers in Sjogren-Larsson syndrome. Ophthalmology 122: 1730-1732, 2015. [PubMed: 25784589] [Full Text: https://doi.org/10.1016/j.ophtha.2015.02.003]
Jagell, S., Gustavson, K.-H., Holmgren, G. Sjogren-Larsson syndrome in Sweden: a clinical, genetic and epidemiological study. Clin. Genet. 19: 233-256, 1981. [PubMed: 7273467] [Full Text: https://doi.org/10.1111/j.1399-0004.1981.tb00704.x]
Jagell, S., Liden, S. Ichthyosis in the Sjogren-Larsson syndrome. Clin. Genet. 21: 243-252, 1982. [PubMed: 6179662] [Full Text: https://doi.org/10.1111/j.1399-0004.1982.tb00758.x]
Jagell, S., Polland, W., Sandgren, O. Specific changes in the fundus typical for the Sjogren-Larsson syndrome: an ophthalmological study of 35 patients. Acta Ophthal. 58: 321-330, 1980. [PubMed: 7415820] [Full Text: https://doi.org/10.1111/j.1755-3768.1980.tb05730.x]
Kousseff, B. G., Matsuoka, L. Y., Stenn, K. S., Hobbins, J. C., Mahoney, M. J., Hashimoto, K. Prenatal diagnosis of Sjogren-Larsson syndrome. J. Pediat. 101: 998-1001, 1982. [PubMed: 7143181] [Full Text: https://doi.org/10.1016/s0022-3476(82)80030-9]
Lake, B. D., Smith, V. V., Judge, M. R., Harper, J. I., Besley, G. T. N. Hexanol dehydrogenase activity shown by enzyme histochemistry on skin biopsies allows differentiation of Sjogren-Larsson syndrome from other ichthyoses. J. Inherit. Metab. Dis. 14: 338-340, 1991. [PubMed: 1770787] [Full Text: https://doi.org/10.1007/BF01811697]
Link, J. K., Roldan, E. C. Mental deficiency, spasticity, and congenital ichthyosis: report of a case. J. Pediat. 52: 712-714, 1958. [PubMed: 13550040] [Full Text: https://doi.org/10.1016/s0022-3476(58)80271-1]
Lossos, A., Khoury, M., Rizzo, W. B., Gomori, J. M., Banin, E., Zlotogorski, A., Jaber, S., Abramsky, O., Argov, Z., Rosenmann, H. Phenotypic variability among adult siblings with Sjogren-Larsson syndrome. Arch. Neurol. 63: 278-280, 2006. [PubMed: 16476818] [Full Text: https://doi.org/10.1001/archneur.63.2.278]
Pigg, M., Jagell, S., Sillen, A., Weissenbach, J., Gustavson, K.-H., Wadelius, C. The Sjogren-Larsson syndrome gene is close to D17S805 as determined by linkage analysis and allelic association. Nature Genet. 8: 361-364, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995. [PubMed: 7894487] [Full Text: https://doi.org/10.1038/ng1294-361]
Rayner, A., Lampert, R. P., Rennert, O. M. Familial ichthyosis, dwarfism, mental retardation, and renal disease. J. Pediat. 92: 766-768, 1978. [PubMed: 641625] [Full Text: https://doi.org/10.1016/s0022-3476(78)80146-2]
Richards, B. W. Congenital ichthyosis, spastic diplegia and mental deficiency. (Letter) Brit. Med. J. 2: 714 only, 1960. [PubMed: 20788940] [Full Text: https://doi.org/10.1136/bmj.2.5200.714]
Rizzo, W. B., Craft, D. A. Sjogren-Larsson syndrome: deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase in cultured fibroblasts. J. Clin. Invest. 88: 1643-1648, 1991. [PubMed: 1939650] [Full Text: https://doi.org/10.1172/JCI115478]
Rizzo, W. B., Dammann, A. L., Craft, D. A., Black, S. H., Henderson Tilton, A., Africk, D., Chaves-Carballo, E., Holmgren, G., Jagell, S. Sjogren-Larsson syndrome: inherited defect in the fatty alcohol cycle. J. Pediat. 115: 228-234, 1989. [PubMed: 2666627] [Full Text: https://doi.org/10.1016/s0022-3476(89)80070-8]
Rizzo, W. B., Dammann, A. L., Craft, D. A. Sjogren-Larsson syndrome: impaired fatty alcohol oxidation in cultured fibroblasts due to deficient fatty alcohol:nicotinamide adenine dinucleotide oxidoreductase activity. J. Clin. Invest. 81: 738-744, 1988. [PubMed: 3343337] [Full Text: https://doi.org/10.1172/JCI113379]
Rizzo, W. B., Dammann, A. L., Craft, D., Black, S., Henderson Tilton, A., Africk, D., Chaves-Carballo, E. Sjogren-Larsson syndrome: deficient fatty alcohol:NAD+ oxidoreductase (FAO) activity in mixed leukocytes. (Abstract) Am. J. Hum. Genet. 41: A16 only, 1987.
Rogers, G. R., Markova, N. G., De Laurenzi, V., Rizzo, W. B., Compton, J. G. Genomic organization and expression of the human fatty aldehyde dehydrogenase gene (FALDH). Genomics 39: 127-135, 1997. [PubMed: 9027499] [Full Text: https://doi.org/10.1006/geno.1996.4501]
Rogers, G. R., Rizzo, W. B., Zlotogorski, A., Hashem, N., Lee, M., Bale, S. J., Compton, J. G. Sjogren-Larsson syndrome (SLS) and fatty aldehyde dehydrogenase (FALDH) genes map to chromosome 17p. (Abstract) Am. J. Hum. Genet. 57: A202 only, 1995.
Rogers, G. R., Rizzo, W. B., Zlotogorski, A., Hashem, N., Lee, M., Compton, J. G., Bale, S. J. Genetic homogeneity in Sjogren-Larsson syndrome: linkage to chromosome 17p in families of different non-Swedish ethnic origins. Am. J. Hum. Genet. 57: 1123-1129, 1995. [PubMed: 7485163]
Selmanowitz, V. J., Porter, M. J. The Sjogren-Larsson syndrome. Am. J. Med. 42: 412-422, 1967. [PubMed: 6018858] [Full Text: https://doi.org/10.1016/0002-9343(67)90269-0]
Sillen, A., Anton-Lamprecht, I., Braun-Quentin, C., Kraus, C. S., Sayli, B. S., Ayuso, C., Jagell, S., Kuster, W., Wadelius, C. Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjogren-Larsson syndrome. Hum. Mutat. 12: 377-384, 1998. [PubMed: 9829906] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)12:6<377::AID-HUMU3>3.0.CO;2-I]
Sillen, A., Jagell, S., Wadelius, C. A missense mutation in the FALDH gene identified in Sjogren-Larsson syndrome patients originating from the northern part of Sweden. Hum. Genet. 100: 201-203, 1997. [PubMed: 9254849] [Full Text: https://doi.org/10.1007/s004390050490]
Sjogren, T., Larsson, T. Oligophrenia in combination with congenital ichthyosis and spastic disorders: a clinical and genetic study. Acta Psychiat. Neurol. Scand. Suppl. 113: 1-112, 1957. [PubMed: 13457946]
Sjogren, T. Oligophrenia combined with congenital ichthyosiform erythrodermia, spastic syndrome and macular retinal degeneration: a clinical and genetic study. Acta Genet. Statist. Med. 6: 80-91, 1956. [PubMed: 13354244]
Willemsen, M. A. A. P., Cruysberg, J. R. M., Rotteveel, J. J., Aandekerk, A. L., Van Domburg, P. H. M. F., Deutman, A. F. Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjogren-Larsson syndrome. Am. J. Ophthal. 130: 782-789, 2000. [PubMed: 11124298] [Full Text: https://doi.org/10.1016/s0002-9394(00)00576-6]
Zaleski, W. A. Congenital ichthyosis, mental retardation and spasticity (Sjogren-Larsson syndrome). Canad. Med. Assoc. J. 86: 951-954, 1962. [PubMed: 14009718]