Recent identification of PANK2 mutations in “HARP syndrome”
(hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa,
pallidal degeneration)[1-3], and of a homozygous CHAC mutation in a
patient with “aprebetalipoproteinemia”[4,5] raises concerns about
continued reference to “prebetalipoprotein” in the context of
neuroacanthocytosis.
The term comes from a bygone era when gel or paper electrophoresis
was used to separate plasma lipoproteins. The “prebetalipoprotein”
fraction migrated faster than low-density lipoprotein (LDL, or
“betalipoprotein”) and in ultracentrifugally-separated plasma corresponds
to particles known today as lipoprotein(a) - Lp(a) - and very-low density
lipoproteins (VLDL). Modern biochemical methods can precisely quantitate
both, eliminating requirement for semi-quantitative electrophoresis.
Currently, isolated low plasma VLDL or
Lp(a) has no pathophysiological consequence. “Hypoprebetalipoproteinemia”
and “aprebetalipoproteinemia” are meaningless from a metabolic point of
view and are absent from the lipoprotein literature. This conflicts with the use of “abetalipoproteinemia” (ABL, Bassen-
Kornzweig syndrome; MIM 200100) and “homozygous hypobetalipoproteinemia”
(FHBL, MIM 107730), which refer to multisystem syndromes mainly due to fat
-soluble vitamin deficiency resulting from MTP or APOB mutations. These
disorders are marked by absence of immunologically detectable
apolipoprotein (apo) B and apo B-containing lipoproteins, including
chylomicrons, VLDL, LDL, and Lp(a). By comparison, HARP was coined in 1992
for a single case observation[2], with only one other case reported. [1,3]
The subsequent neologism “aprebetalipoproteinemia” compounds the
questionable biochemical description, since the apparently
abnormal electrophoretic pattern in the patient[4] would have been
observed in many normal subjects, had more of them been examined.
Demonstration of mutations in PANK2 and CHAC conflicts with the relevance of putative prebetalipoprotein anomalies for the nosology of
neuroacanthocytosis. At one time, ABL was the archetypal
neuroacanthocytosis, and plasma lipoprotein evaluation in new patients
presenting with neurological findings in association with acanthocytosis
was reasonable and apo B immunoquantitation might still sometimes be
helpful. But the distinct clinical pattern of basal ganglia disease (not
seen in ABL and FHBL) in the neuroacanthocytosis syndromes of chorea-
acanthocytosis (MIM 200150), McLeod syndrome (MIM 31485) and Huntington´s
disease-like 2 (MIM 606438) that have normal lipoprotein profiles, has
further uncoupled lipoprotein deficiency from neuroacanthocytosis and
relieved an inclination to stretch biochemical definitions to a presumed
connection. Nevertheless, finding common pathophysiologic pathways
affecting both erythrocytes and neurons is essential in
neuroacanthocytosis research.
The idiosyncratic and imprecise “HARP syndrome”,
“hypoprebetalipoproteinemia” and “aprebetalipoproteinemia” are expendable
– this even more since the clear molecular diagnoses in the three case
observations that gave rise to these terms[1,2,5].
References
1. Houlden H, Lincoln S, Farrer M, Cleland PG, Hardy J, Orrell RW.
Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz
syndromes are allelic. Neurology 2003; 61:1423-1426.
2. Ching KHL, Westaway SK, Gitschier J, Higgins JJ, Hayflick SJ. HARP
syndrome is allelic with pantothenate kinase-associated neurodegeneration.
Neurology 2002; 58:1673-1674.
3. Orrell RW, Amrolia PJ, Heald A, Cleland PG, Owen JS, Morgan-Hughes
JA et al. Acanthocytosis, retinitis pigmentosa, and pallidal degeneration:
A report of three patients, including the second reported case with
hypoprebetalipoproteinemia (HARP syndrome). Neurology 1995; 45:187-192.
4. Bohlega S, Riley W, Powe J, Baynton R, Roberts G.
Neuroacanthocytosis and aprebetalipoproteinemia. Neurology 1998; 50:1912-
1914.
5. Bohlega S, Al Jishi A, Dobson-Stone C, et al. Chorea-acanthocytosis: Clinical and genetic findings in three
families from the Arabian peninsula. Mov Disord 2003; 18:403-407.
Recent identification of PANK2 mutations in “HARP syndrome” (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration)[1-3], and of a homozygous CHAC mutation in a patient with “aprebetalipoproteinemia”[4,5] raises concerns about continued reference to “prebetalipoprotein” in the context of neuroacanthocytosis.
The term comes from a bygone era when gel or paper electrophoresis was used to separate plasma lipoproteins. The “prebetalipoprotein” fraction migrated faster than low-density lipoprotein (LDL, or “betalipoprotein”) and in ultracentrifugally-separated plasma corresponds to particles known today as lipoprotein(a) - Lp(a) - and very-low density lipoproteins (VLDL). Modern biochemical methods can precisely quantitate both, eliminating requirement for semi-quantitative electrophoresis.
Currently, isolated low plasma VLDL or Lp(a) has no pathophysiological consequence. “Hypoprebetalipoproteinemia” and “aprebetalipoproteinemia” are meaningless from a metabolic point of view and are absent from the lipoprotein literature. This conflicts with the use of “abetalipoproteinemia” (ABL, Bassen- Kornzweig syndrome; MIM 200100) and “homozygous hypobetalipoproteinemia” (FHBL, MIM 107730), which refer to multisystem syndromes mainly due to fat -soluble vitamin deficiency resulting from MTP or APOB mutations. These disorders are marked by absence of immunologically detectable apolipoprotein (apo) B and apo B-containing lipoproteins, including chylomicrons, VLDL, LDL, and Lp(a). By comparison, HARP was coined in 1992 for a single case observation[2], with only one other case reported. [1,3] The subsequent neologism “aprebetalipoproteinemia” compounds the questionable biochemical description, since the apparently abnormal electrophoretic pattern in the patient[4] would have been observed in many normal subjects, had more of them been examined.
Demonstration of mutations in PANK2 and CHAC conflicts with the relevance of putative prebetalipoprotein anomalies for the nosology of neuroacanthocytosis. At one time, ABL was the archetypal neuroacanthocytosis, and plasma lipoprotein evaluation in new patients presenting with neurological findings in association with acanthocytosis was reasonable and apo B immunoquantitation might still sometimes be helpful. But the distinct clinical pattern of basal ganglia disease (not seen in ABL and FHBL) in the neuroacanthocytosis syndromes of chorea- acanthocytosis (MIM 200150), McLeod syndrome (MIM 31485) and Huntington´s disease-like 2 (MIM 606438) that have normal lipoprotein profiles, has further uncoupled lipoprotein deficiency from neuroacanthocytosis and relieved an inclination to stretch biochemical definitions to a presumed connection. Nevertheless, finding common pathophysiologic pathways affecting both erythrocytes and neurons is essential in neuroacanthocytosis research.
The idiosyncratic and imprecise “HARP syndrome”, “hypoprebetalipoproteinemia” and “aprebetalipoproteinemia” are expendable – this even more since the clear molecular diagnoses in the three case observations that gave rise to these terms[1,2,5].
References
1. Houlden H, Lincoln S, Farrer M, Cleland PG, Hardy J, Orrell RW. Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic. Neurology 2003; 61:1423-1426.
2. Ching KHL, Westaway SK, Gitschier J, Higgins JJ, Hayflick SJ. HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 2002; 58:1673-1674.
3. Orrell RW, Amrolia PJ, Heald A, Cleland PG, Owen JS, Morgan-Hughes JA et al. Acanthocytosis, retinitis pigmentosa, and pallidal degeneration: A report of three patients, including the second reported case with hypoprebetalipoproteinemia (HARP syndrome). Neurology 1995; 45:187-192.
4. Bohlega S, Riley W, Powe J, Baynton R, Roberts G. Neuroacanthocytosis and aprebetalipoproteinemia. Neurology 1998; 50:1912- 1914.
5. Bohlega S, Al Jishi A, Dobson-Stone C, et al. Chorea-acanthocytosis: Clinical and genetic findings in three families from the Arabian peninsula. Mov Disord 2003; 18:403-407.