(Sphingomyelinase deficiency)

Autosomal recessive transmission. Gangliosidosis caused by deficiency in acid sphingomyelinase, a lysosomal enzyme hydrolysing

sphingomyelin into ceramide.

There are several variants:

-        type A (85 %) (1/500,000) [MIM 257 200]: autosomal recessice transmission of a mutation of the SMPD1 gene (11p15.3) coding  for sphingomyelinase; more frequent in Ashkenazi populations. The enzymatic activity is < 5 % of normal; cholestasis appearing around 2-3 months of age, hepatomegaly; cherry red spot at ophthalmoscopy (30 %), developmental retardation appearing around 1 year of age; frequent pneumonia; gradual deterioration and death in early childhood.

-        type B (1/200,000) [MIM 257 200]: autosomal recessive transmission of a mutation of the SMPD1 (11p15.3) coding for sphingomyelinase; the enzymatic activity is 5 to 10 % of normal; late onset; hepatosplenomegaly without involvement of the CNS; sometimes pancytopenia; foam cells at liver and bone marrow biopsy.

-        type C [MIM 257 220]: a disorder of the export of intralysosomial cholesterol with secondary accumulation of sphingomyelin .  Autosomal recessive transmission of a mutation of the NPC1 protein (18q11) (95 %, C1 form), more rarely of the NPC2 protein (14q24.3) (C2 form) [MIM 607 625]. The physiopathology of the neurological presentation is poorly understood: the neuronal overload concerns especially gangliosides GM1 and GM3 and sphingosine; presence of meganeurites, a juvenile dystrophy and abnormalities at the level of the GABAergic and glutaminergic synapses . "Navy Blue" histiocytes at bone marrow biopsy. Treatment is symptomatic; experimental treatment with miglustat.

There are 5 clinical forms classified according to the age of onset:

+        perinatal: sometimes fetal ascites, hepatosplenomegaly, cholestatic jaundice and hepatocellular failure with early death . Less severe forms: prolonged cholestatic jaundice, giant cell hepatitis. In case of NPC2 mutation: respiratory involvement with interstitial lung disease and clinical picture of alveolar lipoproteinosis

+        early infantile: onset before 2 years of age; hypotonia, delay or stagnation of acquisitions, spasticity of the limbs evolving toward spastic tetraparesis; leukodystrophy at MRI. Hepatosplenomegaly. Vertical supranuclear gaze palsy, crises of gelastic cataplexy [sudden loss of muscle tone , without loss of consciousness, triggered by an emotional stimulus, e.g. laughter ; the loss of tone may involve the legs, neck or jaw. Cataplexy manifests as sudden falls, sudden head drop or jaw drop, triggered by laughing. Death around 5 years of age.

+        late infantile : onset between 2 and 6 years of age; appearance of neurological signs: hypotonia, slow motion,  drooling, dysphagia with aspiration, cognitive impairment. Severe epilepsy in 30-50 % of cases. Death before the age of 15 years

+        juvenile: onset between 6 and 15 years of age; appearance of poor motor coordination; epilepsy; gelastic cataplexy; vertical supranuclear gaze palsy; cerebellar disorders  (ataxia), swallowing disorders, dysarthria, psychiatric disorders (psychosis, schizophrenia, progressive dementia), and eventually a bedridden state

+        teenager/adult: onset after 15 years of age, learning difficulties, gelastic cataplexy; vertical supranuclear gaze palsy, dementia, epilepsy, cerebellar disorders (ataxia), swallowing disorders, dysarthria

Experimental treatment for the C1 forms: regular intrathecal injections of 2-hydroxypropyl-betacyclodextrin.

-        type D [MIM 257 220]: G992W mutation of the NPC1 gene (Nova Scotian form): that form is very similar to the C1 form in a group of Nova Scotian patients. Cholestasis and hepatomegaly; vertical supranuclear ophthalmoplegia and "Navy Blue" histiocytes at bone marrow biopsy. Progressive neurological deterioration between 5 and 9 years of age (dysarthria, ataxia, convulsions).

-        type E: late form without neurological signs, beginning between 20 and 40 years of age. Splenomegaly with thrombocytopenia.

Anesthetic implications:

check liver function and platelets count. C Form: hypoplaquettosis, severe epilepsy, psychomotor retardation, aspiration, risk of difficult intubation and aspiration. Risk of hyper - and hypothermia during MRI.

References : 

-        Bujok SS, Bujok G, Knapik P. 
Niemann-Pick disease : a rare problem in anaesthesiological practice. 
Paediatr Anaesth 2002; 12: 806-8.

-         MiaoN, Lu X, O’Grady MP, Yanjanin N, Porter FD, Quezado ZMN. 
Niemann-Pick disease type C: implications for sedation and anesthesia for diagnostic procedures. 
J Child Neurol 2013;27: 1541-6.  

-        Schilling T, Kozian A, Pfau G, et al.
Anesthetic management of a patient with NiemannPick type B disease undergoing cardiac surgery.
J Cardiothorac Vasc Anesth. 2007; 21:428-31 

-        Ulloa ML, Froyshteter AB, Kret LN, Chang DP, Sarah GE, McCarthy RJ, Barnes SD,  Berry-Kravis EM.
Anesthetic management of pediatric patients with Niemann-Pick disease type C for intrathecal 2-hydroxypropyl-â-cyclodextrin injection.
Pediatr Anesth 2020; 30 : 766-72.

-        Al-Shamrani  A, Al-Shamrani K, Bin Mahfoudh A , Mohamed AS, Mohamed S. A
Niemann-Pick Disease Type C2 with severe pulmonary involvement and limited therapeutic options: a case report.
Children 2022, 9, 1811. https://doi.org/10.3390/children9121811

Updated: January 2023