RSS-Feed abonnieren
DOI: 10.1055/s-2003-44668
Georg Thieme Verlag Stuttgart · New York
Niemann-Pick Disease Type A and B are Clinically but also Enzymatically Heterogeneous: Pitfall in the Laboratory Diagnosis of Sphingomyelinase Deficiency Associated with the Mutation Q292 K
Publikationsverlauf
Received: June 3, 2003
Accepted after Revision: September 24, 2003
Publikationsdatum:
18. Dezember 2003 (online)
![](https://www.thieme-connect.de/media/neuropediatrics/200306/lookinside/thumbnails/10.1055-s-2003-44668-1.jpg)
Abstract
This study describes a diagnostic pitfall in the laboratory diagnosis of patients with sphingomyelinase deficiency (SMD; Niemann-Pick disease types A and B; NPA and NPB), in cases where sphingomyelinase activity was not determined with sphingomyelin as the natural enzymic substrate. Four of 24 SMD patients studied had falsely normal or enhanced activity, when a so-called artificial sphingomyelinase substrate, 2-N-(hexadecanoyl)-amino-4-nitrophenyl phosphorylcholine (HNP), was used, whereas SMD was clear with the sphingomyelin substrate. Those four patients had the Q292 K mutation of the acid sphingomyelinase gene (SMPD1) on at least one allele. Three of the four patients (no data available from one) experienced only late-infantile or juvenile, though distinct, neurological involvement, where learning disabilities, hypo- or areflexia or mild ataxia were initial signs. The laboratory pitfall with HNP substrate, which is used in many laboratories, raises the risk that some SMD patients are overlooked, and it prevents the consideration of a late-manifesting neurological course in some patients as well as the planning of enzyme substitution therapy in non-neurological SMD (NPB) patients. Since classical NPB is very rare, it is suggested that SMD patients with late- or mild-manifesting neurological symptoms should better be assigned to additional SMD subgroups than grouped with NPB.
Key words
Niemann-Pick disease - classification - mutation - sphingomyelinase - synthetic substrate
References
- 1 Bauer P, Knoblich R, Bauer C, Finckh U, Hufen A, Kropp J, Braun S, Kustermann-Kuhn B, Schmidt D, Harzer K, Rolfs A. NPC1: Complete genomic sequence, mutation analysis and characterization of haplotypes. Hum Mutat. 2002; 19 30-38
- 2 Elleder M, Nevoral J, Špičácová V, Hyniová H, Kraus J, Krásný J, Vanier M T. A new variant of sphingomyelinase deficiency (Niemann-Pick): visceromegaly, minimal neurological lesion and low in vivo degradation rate of sphingomyelin. J Inherit Metab Dis. 1986; 9 357-366
- 3 Gal A E, Brady R O, Hibbert S R, Pentchev P G. A practical chromogenic procedure for the detection of homozygotes and heterozygous carriers of Niemann-Pick disease. N Engl J Med. 1975; 293 632-636
- 4 Gal A E, Fash F J. Synthesis of 2-N-(hexadecanoyl)-amino-4-nitrophenyl phosphorylcholine hydroxide, a chromogenic substrate for assaying sphingomyelinase activity. Chem Phys Lipids. 1976; 16 71-79
- 5 Harzer K, Ruprecht K W, Seuffer-Schulze D, Jans U. Morbus Niemann-Pick Typ B - enzymatisch gesichert - mit unerwarteter retinaler Beteiligung. Albrecht v Graefes Arch klin exp Ophthal. 1978; 206 79-88
- 6 Kopitz J, Harzer K, Kohlschütter A, Zöller B, Blenck N, Cantz M. Methylamine accumulation in cultured cells as a measure of the aqueous storage compartment in the laboratory diagnosis of genetic lysosomal diseases. Am J Med Genet. 1996; 53 198-202
- 7 Levade T, Salvayre R, Douste-Blazy L. Comparative hydrolysis of sphingomyelin and 2-N-(hexadecanoyl)-amino-4-nitrophenyl-phosphorylcholine by normal human brain homogenate at acid and neutral pH. J Neurochem. 1983; 40 1762-1764
- 8 Martin J-J, Philippart M, Van Hauwaert J, Callahan J W, Deberdt R. Niemann-Pick disease (Crocker's group A). Late onset and pigmentary degeneration resembling Hallervorden-Spatz syndrome. Arch Neurol. 1972; 27 45-51
- 9 Miller S A, Dykes D D, Polesky H F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988; 16 1215
- 10 Miranda S R, He X, Simonaro C M, Gatt S, Dagan A, Desnick R I, Schuchmann E H. Infusion of recombinant human acid sphingomyelinase into Niemann-Pick disease mice leads to visceral, but not neurological, correction of the pathophysiology. FASEB J. 2000; 14 1988-1995
-
11 Patterson M C, Vanier M T, Suzuki K, Morris J A, Carstea E, Neufeld E B, Blanchette-Mackie J E, Pentchev P G.
Niemann-Pick disease type C: a lipid trafficking disorder. Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. New York; McGraw-Hill 2001: 3611-3633 - 12 Pavlů H, Elleder M. Two novel mutations in patients with atypical phenotypes of acid sphingomyelinase deficiency. J Inherit Metab Dis. 1997; 20 615-616
-
13 Schuchman E H, Desnick R I.
Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies. Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. New York; McGraw-Hill 2001: 3589-3610 - 14 Simonaro C M, Desnick R J, McGovern M M, Wasserstein M P, Schuchman E H. The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations. Am J Hum Genet. 2002; 71 1413-1419
- 15 Sogawa H, Horino K, Nakamura F, Kudoh T, Oyanagi K, Yamanouchi T, Minami R, Nakao T, Watanabe A, Matsuura Y. Chronic Niemann-Pick disease with sphingomyelinase deficiency in two brothers with mental retardation. Eur J Pediatr. 1978; 128 235-240
Prof. Dr. K. Harzer
Universitäts-Kinderklinik
Neurometabolisches Labor
Hoppe-Seyler-Straße 1
72076 Tübingen
Germany
eMail: Ingeborg.Kraegeloh-Mann@med.uni-tuebingen.de