Table 3.

Disorders with Ataxia in the Differential Diagnosis of PNPLA6 Disorders

Gene(s)DiffDx DisorderMOIClinical Features of DiffDx DisorderDistinguishing Features
ANGPTL3
APOB
MTTP 1		Abetalipoproteinemia & familial hypobetalipoproteinemia (OMIM 615558, 605019)ARRP, progressive ataxia, steatorrhea, demyelinating neuropathy, dystonia, extrapyramidal signs, spastic paraparesis (rare) 2PNPLA6 disorders w/retinopathy typically incl anterior pituitary hormone deficiency.
ATXN7 SCA7 ADProgressive cerebellar ataxia (incl dysarthria & dysphagia) & a cone-rod retinal dystrophy w/progressive central visual loss → blindness in affected adults 3PNPLA6 disorders present w/widespread rod-cone or cone-rod retinal degeneration & can incl hypogonadism.
MT-ATP6
MT-ND6
MT-TV 		NARP (See mtDNA-Associated Leigh Syndrome Spectrum.)MatChildhood-onset disease most often characterized by proximal neurogenic muscle weakness w/sensory neuropathy, ataxia, learning difficulties, & pigmentary retinopathyPNPLA6 disorders w/retinopathy typically incl anterior pituitary hormone deficiency.
OTUD4
RNF216 4		RNF216/OTUD4 ataxia-hypogonadismARAtaxia w/hypogonadism & dementiaPNPLA6 disorders do not typically incl dementia.
PEX7
PHYH 		Refsum disease ARAnosmia (a universal finding) & early-onset RP w/variable combinations of chronic polyneuropathy, deafness, cerebellar ataxia, & ichthyosis; cardiac conduction disorders are common.Hearing loss has not been reported in PNPLA6 disorders.
POLR3A
POLR3B
POLR1C 		POLR3 leukodystrophy ARHypomyelinating leukodystrophy w/neurologic (cerebellar, extrapyramidal, pyramidal, & cognitive) & non-neurologic (dental, endocrine, & ocular) featuresPNPLA6 disorders are not assoc w/dental abnormalities or leukodystrophy.
SIL1 Marinesco-Sjögren syndrome (MSS)ARCerebellar ataxia w/cerebellar atrophy, early-onset cataracts, mild-to-severe ID, hypotonia, muscle weakness, & hypergonadotropic hypogonadism; after age 7 yrs. MSS is invariably assoc w/the combination of a cerebellar syndrome, chronic myopathy, & cataracts. 5Myopathy & cataracts have not been reported in PNPLA6 disorders.
SPART Troyer syndrome ARProgressive spastic paraparesis, dysarthria, pseudobulbar palsy, distal amyotrophy, motor & cognitive delays, short stature, & subtle skeletal abnormalitiesSkeletal abnormalities have not been reported in PNPLA6 disorders.
STUB1 Autosomal recessive SCA 16 (See Hereditary Ataxia Overview.)ARAtaxia w/cerebellar atrophy & variable cognitive impairment, hypogonadism, &/or pyramidal tract involvement 6PNPLA6 disorders are characterized by more rapid disease progression & incl chorioretinal dystrophy.
TTPA Ataxia w/vitamin E deficiency (AVED)AREarly-onset progressive ataxia, clumsiness of the hands, loss of proprioception (esp of vibration & joint position sense), areflexia 7PNPLA6 disorders often have less severe loss of proprioception & can incl hypogonadism.
TWNK Infantile-onset SCA (IOSCA) (OMIM 271245)ARSevere, progressive neurodegenerative disorder w/normal development until age 1 yr, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, & athetosis; hypergonadotropic hypogonadism becomes evident in females by adolescence.IOSCA usually starts in early childhood & is mostly accompanied by athetosis, deafness, ophthalmoplegia, &/or epilepsy.

AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; Mat = Maternal; MOI = mode of inheritance; NARP = neurogenic muscle weakness, ataxia, and retinitis pigmentosa; RP = retinitis pigmentosa; SCA = spinocerebellar ataxia

1.

Abetalipoproteinemia is caused by biallelic pathogenic variants in MTTP; familial hypobetalipoproteinemia is caused by biallelic pathogenic variants in APOB or ANGPTL3.

2.

Hypocholesterolemia and reduced lipid-soluble vitamins in serum are due to defective intestinal absorption of lipids.

3.

Onset of SCA7 in early childhood or infancy has an especially rapid & aggressive course often associated with failure to thrive & regression of motor milestones.

4.

Biallelic pathogenic variants in RNF216 or, in one family, biallelic pathogenic variants in both RNF216 and OTUD4, are causative [Margolin et al 2013].

5.
6.
7.

The principal criterion for diagnosis of AVED is a Friedreich ataxia-like neurologic phenotype combined with markedly reduced plasma vitamin E (α-tocopherol) concentration in the absence of known causes of malabsorption.

From: PNPLA6 Disorders

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