Table 4.

Genes of Interest in the Differential Diagnosis of VPS13A Disease

Gene(s)DisorderMOIFeatures of Disorder
Overlapping w/VPS13A DiseaseDistinguishing from VPS13A Disease
ANGPTL3
APOB 		Hypobetalipoproteinemia (See APOB-Related Familial Hypobetalipoproteinemia.)AR
  • Acanthocytosis
  • Dysarthria, neuropathy, & areflexia
  • Absence of basal ganglia movement disorder
  • Hallmark findings of pigmentary retinopathy, vitamin E deficiency, & steatorrhea
  • Spinocerebellar syndrome & sensorimotor neuropathy
ATN1 DRPLA AD
  • Choreoathetosis
  • Epilepsy
Ataxia
ATP7B Wilson disease AR
  • ↑ liver enzymes
  • Tremor, poor coordination, loss of fine motor control, chorea, & choreoathetosis OR rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement)
  • Psychiatric disturbance (depression, neurotic behaviors, disorganization of personality &, occasionally, intellectual deterioration)
  • Low serum copper & ceruloplasmin concentrations & ↑ urinary copper excretion, esp after chelator challenging
  • Prominent MRI abnormalities during disease progression
ELAC2 Combined oxidative phosphorylation deficiency-17 (COXPD17) (OMIM 615440)ARChorea, psychosis, acanthocytosis 1Apart from a single adult case w/ELAC2 pathogenic variant, 1 clinical findings & presentation age (early childhood) in COXPD17 differ greatly from VPS13A disease.
HPRT1 Lesch-Nyhan disease (See HPRT1 Disorders.)XL
  • Cognitive & behavioral disturbances
  • Self-injurious behavior (biting of lips, cheeks fingers, hands; head/limb banging)
  • Neurologic dysfunction (dystonia, choreoathetosis, opisthotonos)
  • Age at manifestation (early childhood) very different from VPS13A disease
  • Hyperuricemia
HTT Huntington disease (HD)AD
  • Chorea syndrome, changes of personality & behavior, & imaging findings in HD & VPS13A disease are almost identical.
  • Parkinsonism is typical for juvenile HD (Westphal variant) & transition to parkinsonism is not uncommon in late-stage HD.
  • Seizures are much more common in VPS13A disease than in HD.
  • ↑ serum concentrations of CK or liver enzymes & acanthocytosis are unusual for HD.
  • ↓ ankle reflexes are more prevalent in VPS13A disease.
  • The neuropathology of HD is more widespread & involves the cerebral cortex.
JPH3 Huntington disease-like 2 (HDL2)ADHuntingtonism typically presenting in midlife w/progression to death over 10-20 yrs
  • Acanthocytes are not present in great majority of affected persons.
  • Serum CK is normal.
  • Myopathy & seizures are absent.
  • HDL2 has been described exclusively in persons w/African ancestry.
MTTP Abetalipoproteinemia AR
  • Acanthocytosis
  • Dysarthria, neuropathy, & areflexia
  • Hallmark findings: presence of pigmentary retinopathy, vitamin E deficiency, steatorrhea, & absence of basal ganglia movement disorder
  • Spinocerebellar syndrome & sensorimotor neuropathy
PANK2 Pantothenate kinase-associated neurodegeneration (PKAN) (See also Neurodegeneration with Brain Iron Accumulation Disorders Overview.)AR
  • Early childhood onset of progressive dystonia, dysarthria, rigidity, & choreoathetosis
  • "Atypical" presentation: onset at age >10 yrs, prominent speech defects, psychiatric disturbances, & more gradual progression of disease
  • Acanthocytes often observed
  • "Eye of the tiger" MRI finding (identified on transverse images of globus pallidus as central region of hyperintensity surrounded by rim of hypointensity) in PKAN
  • Much younger age of disease onset
XK McLeod neuroacanthocytosis syndrome (also referred to as McLeod syndrome [MLS] or XK disease 2)XL
  • CNS manifestations (movement disorder, cognitive impairment, & psychiatric symptoms)
  • Neuromuscular manifestations (mostly subclinical sensorimotor axonopathy, muscle weakness, or atrophy)
  • Red blood cell acanthocytosis & compensated hemolysis
  • Usually later onset in MLS of some features shared w/VPS13A disease (e.g., huntingtonism, feeding dystonia, & head drops)
  • The McLeod blood group phenotype 3 distinguishes MLS from VPS13A disease (in which Kell blood group antigen expression is normal).
  • Malignant arrhythmias & cardiomyopathy are common.

AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; XL = X-linked

1.
2.

Because the term "neuroacanthocytosis" refers to several genetically and phenotypically distinct disorders, the terms McLeod syndrome or XK disease are preferred by the authors [Walker & Danek 2021; Authors, personal observation].

3.

Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod; "McLeod blood group phenotype") that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. Note: Transfusions of Kx-positive blood products should be avoided in persons w/the McLeod blood group phenotype. Kx-negative blood or, if possible, banked autologous or homologous blood should be used for transfusions.

From: VPS13A Disease

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