Cerebral Lipidosis

Cerebral lipidosis, now replaced by the term cerebral sphingolipidoses (lysosomal lipid storage diseases or just sphingolipidoses are also used), is a group of metabolic disorders that arise from genetic mutations (predominantly autosomal recessive), which promote accumulation of lipids (sphingomyelins) and other associated products in the brain and the central nervous system (CNS) [1] [2] [3] [4]. One of the most important features of these conditions is a severe neonatal or infantile form of the disease, distinguished by marked neurological deterioration, convulsions, both upper and lower motor neuron deficits, and weakness, all frequently leading to death in the first few years of life [1] [4] [5] [6] [7]. On the other hand, juvenile and adult forms show a generally slower clinical course with less severe symptoms of neurodegeneration [1] [5] [6] [7]. The following conditions are included in this group [1] [3] [4] [8]:

• GM1 gangliosidosis - Stems from autosomal recessive mutations in the GM1-β-galactosidase gene resulting in the deficiency of the GM1-β-galactosidase enzyme [1].
• GM2 Gangliosidosis - Hexosaminidase A (HEX A) deficiency leads to Tay-Sachs disease (or GM2 gangliosidosis, due to the buildup of GM2 ganglioside) that has a similar clinical presentation to other cerebral lipidoses.
• Sandhoff disease - Mutations in the hexosaminidase B (HEXB) gene lead to a very early onset of psychomotor retardation (many patients present before 9 months of age) and death [9].
• Metachromatic leukodystrophy (MLD) - Deficiency of the arylsulphatase A (ASA) gene is the main pathological event in MLD, which causes a demyelinating form of cerebral lipidosis [1].
• Krabbe disease - Similarly to MLD, Krabbe disease causes a severe and often fatal demyelinating disease in infancy, whereas a much longer life expectancy is seen with juvenile and adult forms [1] [5].
• Gaucher disease - Described as the most common sphingolipidosis (diagnosed in approximately 1 per 50,000-200,000 births), Gaucher disease predominantly presents as a milder form (type I), but a severe neonatal course (type II) and a juvenile onset of intermediate complaints (type III) are described as well [1]. In addition to central nervous system (CNS) complaints, hepatosplenomegaly and anemia/thrombocytopenia are typically encountered [1].
• Niemann-Pick disease - Three types of Niemann-Pick disease exist in the literature - types A and B arise from mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene that result in the accumulation of sphingomyelin in cells [1]. Type A is universally fatal in infancy, whereas type B can present with a highly variable spectrum of symptoms, but a normal life expectancy can be observed without prominent CNS symptoms [1]. Conversely, Niemann-pick disease type C (NPC) is a lysosomal storage disease caused by defects in cholesterol transport, but it also results in sphingomyelin accumulation, with vertical gaze palsy being a clinical hallmark in addition to CNS symptoms [1] [6].

The diagnosis of cerebral lipidoses must be suspected when a neonatal or infantile onset of progressive neurological and psychomotor decline is observed. But in order to confirm clinical suspicion, a detailed patient history and a comprehensive physical examination are mandatory steps. Given the autosomal recessive pattern of inheritance, a positive family history may provide useful information. As soon as a presumptive diagnosis is made, directed genetic and biochemical studies should be employed. Several laboratory techniques have been described, but a rapid liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) assay provides a quantitative method used to evaluate lysosphingolipids in blood. This is a superior procedure that provides enough information to confirm lipid accumulation [4] [5] [6] [7] [8]. Molecular genetic testing (DNA sequencing) that allows identification of specific gene mutations can be performed to verify the diagnosis [5] [6] [7] [9].

1. Schulze H, Sandhoff K. Lysosomal Lipid Storage Diseases. Cold Spring Harb Perspect Biol. 2011;3(6):a004804.
2. Rieger D, Auerbach S, Robinson P, Gropman A. Neuroimaging of lipid storage disorders. Dev Disabil Res Rev. 2013;17(3):269-282.
3. Ozkara HA, Topçu M. Sphingolipidoses in Turkey. Brain Dev. 2004 Sep;26(6):363-366.
4. Platt FM, Boland B, van der Spoel AC. Lysosomal storage disorders: The cellular impact of lysosomal dysfunction. J Cell Biol. 2012;199(5):723-734.
5. Pavuluri P, Vadakedath S, Gundu R, Uppulety S, Kandi V. Krabbe Disease: Report of a Rare Lipid Storage and Neurodegenerative Disorder. Muacevic A, Adler JR, eds. Cureus. 2017;9(1):e949.
6. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5:16.
7. Kaback MM, Desnick RJ. Hexosaminidase A Deficiency. 1999 Mar 11 [Updated 2011 Aug 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
8. Polo G, Burlina AP, Kolamunnage TB, Zampieri M, Dionisi-Vici C, Strisciuglio P, Zaninotto M, Plebani M, Burlina AB Diagnosis of sphingolipidoses: a new simultaneous measurement of lysosphingolipids by LC-MS/MS. Clin Chem Lab Med. 2017;55(3):403-414.
9. Delnooz CC, Lefeber DJ, Langemeijer SM, et al. New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype. J Neurol Neurosurg Psychiatry. 2010;81(9):968-972.