Table 2.

Genes of Interest in the Differential Diagnosis of McLeod Neuroacanthocytosis Syndrome (MLS)

GeneDisorderMOIClinical Features of Differential Diagnosis Disorder
Overlapping w/MLSDistinguishing from MLS
HTT Huntington disease AD
  • May appear indistinguishable from MLS
  • Progressive choreatic mvmt disorder
  • Cognitive & psychiatric disturbances
  • Anticipation
  • Absence of acanthocytes, seizures, myopathy, & cardiomyopathy
  • Normal CK
VPS13A Chorea-acanthocytosis AR
  • Progressive mvmt disorder (primarily chorea)
  • Subclinical myopathy → progressive distal muscle wasting & weakness
  • Mental changes
  • Seizures
  • Progressive cognitive & behavioral changes that resemble a frontal lobe syndrome
  • Dystonia affecting trunk & esp oral region & tongue → dysarthria & serious dysphagia → weight loss
  • May present w/a parkinsonian syndrome
  • Habitual tongue & lip biting characteristic
  • Cardiac disease less severe, if present
Other disorders
ATN1 DRPLA AD
ATP7B Wilson disease AR
ATXN3 SCA3 AD
CP Aceruloplasminemia 1ARAcanthocytosis has been reported in 1 person w/aceruloplasminemia but this does not appear to be a consistent finding. 2
DYT3 X-linked dystonia-parkinsonism (DYT3, DYT-TAF1, Lubag)XL
FTL Neuroferritinopathy 1AD
JPH3 Huntington disease-like 2 AD
  • May appear indistinguishable from MLS
  • Progressive choreatic movement disorder
  • Cognitive & psychiatric disturbances
Acanthocytosis was initially reported; subsequent systematic studies have not validated that observation. 3
HPRT1 Lesch-Nyhan disease XL
NKX2-1 Benign hereditary chorea (See NKX2-1-Related Disorders.)AD
PANK2 PKAN; incl HARP 1, 4AR
  • Progressive dystonia
  • Dysarthria
  • Rigidity
  • In ~25% of persons: "atypical" presentation w/onset age >10 yrs, prominent speech defects, psychiatric disturbance, & more gradual disease progression
  • In ≥8%: acanthocytosis
  • Chorea not observed
  • Usually childhood or adolescent onset
  • Basal ganglia iron deposition
  • "Eye of the tiger" sign on MRI characteristic
  • Pigmentary retinopathy
PLA2G6 PLA2G6-associated neurodegeneration 1
(infantile neuroaxonal dystrophy; Karak syndrome)		AR
PRNP Huntington disease-like 1 (See Genetic Prion Disease.)ADPhenotype may be indistinguishable from Huntingrton disease.
  • Rapidly progressive course
  • No hematologic, neuromuscular, or cardiac manifestations
TBP SCA17 AD
Lipid malabsorption syndromes with acanthocytosis 5 affecting spinal cord, cerebellum, & PNS 6
ANGPTL3 Hypobetalipoproteinemia type 2 (OMIM 605019) 6AR
  • Acanthocytosis
  • Dysarthria
  • Neuropathy
  • Areflexia
  • Pigmentary retinopathy
  • No basal ganglia involvement
APOB APOB-related familial hypobetalipoproteinemia 6AR
MTTP Abetalipoproteinemia (Bassen-Kornzweig syndrome) 6AR

AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DRPLA = dentatorubral-pallidoluysian atrophy; MOI = mode of inheritance; PKAN = pantothenate kinase-associated neurodegeneration; PNS = peripheral nervous system; SCA = spinocerebellar ataxia; XL = X-linked

1.
2.
3.
4.

HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) syndrome is allelic with PKAN [Ching et al 2002, Houlden et al 2003]. The continued use of this term is discouraged particularly since "hypoprebetalipoproteinemia" is not a meaningful entity [Walker et al 2021].

5.

Neurologic disorders associated with RBC acanthocytosis have been summarized as neuroacanthocytosis syndromes [Danek et al 2004, Danek et al 2005, Jung et al 2011].

6.

Neurologic findings include [Kane & Havel 1995, Tarugi & Averna 2011]:
▪ A progressive spinocerebellar degeneration with gait ataxia, dysmetria, and dysarthria;
▪ A demyelinating sensorimotor and axonal peripheral neuropathy with hyporeflexia and diminished vibration and position sense;
▪ Pyramidal tract signs (rare);
▪ Cranial nerve involvement (rare).

From: McLeod Neuroacanthocytosis Syndrome

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