Recommendations for patient screening in ultra-rare inherited metabolic diseases: what have we learned from Niemann-Pick disease type C?

Table 1 Comparison of NP-C with other, similar ultra-rare IEMs

	NP-C	Tay-Sachs disease	MEGDEL syndrome	Krabbe disease	Gaucher disease type 3
Biological and biomarker features
Genes	NPC1/NPC2	HEXA	SERAC1	GALC	GBA
Cellular markers	Filipin staining	–	Filipin staining, phosphatidylglycerol 34:1/36:1 levels [68, 69]	–	–
Fluid/enzymatic diagnostic biomarkers	Plasma oxysterols, bile acids, and lysosphingolipids (e.g. Lyso-SM-509)	Plasma lyso GM2 ganglioside; plasma HEXA activity	Urine 3-MGA/3-MGC	Plasma GALC activity	Plasma glucocerebrosidase activity, lyso-GB1
Clinical manifestations	Adult ataxia, VSSP, dystonia, myoclonus, dysphagia, dysarthria, cataplexy, psych. problems, visceral symptoms^a	SEM abnormalities, dysarthria, ataxia, dystonia, lower MND, myoclonus, epilepsy, psych. problems	Hearing loss, dystonia, spasticity, dysarthria	Vision/hearing loss, ataxia, dysmetria, spasticity	Hepatosplenomegaly, thrombocytopenia, anaemia/fatigue, bone abnormalities, HSGP, ataxia, parkinsonism, epilepsy
Rarity and range of clinical features mandating a need for screening studies
Ultra-rare	Yes	Yes	Yes	Yes	Yes
Variable phenotype, mainly neurological	Yes	Yes	Yes	Yes	Yes
Onset from infancy to adulthood	Yes	Yes	Yes [69]	Yes	Yes

^aOther, non-specific neurological manifestations can also be present. GALC galactocerebrosidase, GBA beta-glucocerebrosidase, HEXA hexosaminidase A, HSGP horizontal supranuclear gaze palsy, MEGDEL 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 3-MGA 3-methylglutaconic acid, 3-MGC 3-methylglutaric acid, MND motor neurone disease, Psych. psychiatric, SEM saccadic eye movement, SERACC1 Serine Active Site Containing protein 1, VSSP vertical supranuclear saccade palsy

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