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Combined Saposin Deficiency

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Combined Saposin Defiency is a very rare metabolic and genetic disorder that is caused by the mutation in a gene PSAP. This disease belongs to Lysosomal Storage Diseases(LSDs). Because of complete saposin deficiency, it can cause clinical features of 4 diseases(Gaucher’s Disease, Metachromatic Leukodystrophy, Farber’s Disease, Krabbe’s Disease) to be apparent.

Medical condition
Combined Saposin Deficiency
Other namesProsaposin Defiency, Combined Sap Deficiency, PSAPD
PSAPD is inherited in a Autosomal Recessive fashion

Cause

PSAPD is caused by mutations in a PSAP gene, which is located on the long arm of chromosome 10 (10q22.1).

A photo showing structure of Prosaposin

Symptoms

Symptoms usually start in infancy or in neonatal age. The signs of this disease are respiratory failure, hepatosplenomegaly, poor feeding, myoclonus, hyperkinetic movements, clonic seizures, leukodystrophy, hypotonia, abnormality of eye movement and a neuronal loss.

Optic atrophy was only reported in 1 patient

Pathophysiology

It’s known that Prosaposin is a precursor of a Saposin A,B,C,D. Saposin A is needed to activate galactocerbroside hydrolysis, Saposin B for sulphatide hydrolysis activation, Saposin C for glucocerebroside hydrolysis, Saposin D might activate hydrolysis of ceramide.

According to one study, Prosaposin might be involved in neuron and glial protection by extracellular secretion and activation of some G coupled-protein receptors.

In conclusion, PSAPD might not only cause accumulation of some sphingolipids, but also it can cause neuronal survival crisis (by mechanism mentioned above).

Prevalence

Prevalence is unknown but 10 cases of this diseases had been reported.

Diagnosis

The study of sphingolipids in urine sediment (It shows combined massive elevation of globotriaosylceramide (Gb3), sulphatide and some other sphingolipids) might be useful for a correct orientation towards diagnosis, also bone marrow/liver’s biopsies usually show Gaucher-like macrophages. For the final diagnosis PSAP gene would be tested for mutations.

Prognosis

Unfortunately, prognosis is poor for this disease.

History

It was first reported by Harzer et al. in 1989

Reference

  1. ^ "Entry - #611721 - COMBINED SAPOSIN DEFICIENCY; PSAPD - OMIM". omim.org. Retrieved 2025-01-07.
  2. Hulková, H.; Cervenková, M.; Ledvinová, J.; Tochácková, M.; Hrebícek, M.; Poupetová, H.; Befekadu, A.; Berná, L.; Paton, B.C.; Harzer, K.; Böör, A.; Smíd, F.; Elleder, M. (2001-04-15). "A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation". Human Molecular Genetics. 10 (9): 927–940. doi:10.1093/hmg/10.9.927. ISSN 0964-6906. PMID 11309366.
  3. ^ Bhat, Vivek; Thergaonkar, R. W.; Thakur, Manisha; Rajkamal, T. (2023-03-01). "Combined saposin deficiency: A rare occurrence". Medical Journal Armed Forces India. 79 (2): 238–240. doi:10.1016/j.mjafi.2021.01.024. ISSN 0377-1237. PMC 10037043. PMID 36969110.
  4. ^ "Orphanet: Encephalopathy due to prosaposin deficiency". www.orpha.net. Retrieved 2025-01-07.
  5. "Orphanet: Clinical signs and symptoms". www.orpha.net. Retrieved 2025-01-07.
  6. "Saposins: structure, function, distribution, and molecular genetics".
  7. Gebai, Ahmad; Gorelik, Alexei; Nagar, Bhushan (2018-11-01). "Crystal structure of saposin D in an open conformation". Journal of Structural Biology. 204 (2): 145–150. doi:10.1016/j.jsb.2018.07.011. ISSN 1047-8477.
  8. Meyer, Rebecca C.; Giddens, Michelle M.; Coleman, Brilee M.; Hall, Randy A. (2014-10-17). "The protective role of prosaposin and its receptors in the nervous system". Brain Research. 1585: 1–12. doi:10.1016/j.brainres.2014.08.022. ISSN 0006-8993.
  9. Harzer, K.; Paton, B. C.; Poulos, A.; Kustermann-Kuhn, B.; Roggendorf, W.; Grisar, T.; Popp, M. (1989-10-01). "Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: Biochemical signs of combined sphingolipidoses". European Journal of Pediatrics. 149 (1): 31–39. doi:10.1007/BF02024331. ISSN 1432-1076.