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BRIEF COMMUNICATIONS: H. Houlden, S. Lincoln, M. Farrer, P.G. Cleland, J. Hardy, and R.W. Orrell Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic Neurology 2003; 61: 1423-1426 [Abstract] [Full text] [PDF]

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Reply to Danek et al

Richard W Orrell, Henry Houlden, Jim S Owen   (18 February 2004)

Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic

Adrian Danek, MD, Robert A. Hegele, MD, FRCP, FACP   (18 February 2004)

Reply to Danek et al 18 February 2004
Richard W Orrell, Clinical Neurosciences, Royal Free and University College Medical School, University College London Rowland Hill Street, London NW3 2PG, England, Henry Houlden, Jim S Owen Send Correspondence to journal: Re: Reply to Danek et al r.orrell{at}rfc.ucl.ac.uk Richard W Orrell, et al.	We thank Danek et al for their comments. “HARP” describes a clinical syndrome, identified in two patients, from two different families, both of whom have PANK2 mutations.[1-3] Neuroacanthocytosis with “aprebetalipoproteinemia”, and mutations of a different gene - the gene for choreoacanthocytosis, chorein – have been described in another patient. [4,5] The pattern recognition of clinical syndromes by neurologists is important especially due to the increasing number and range of genetic abnormalities which may account for similar syndromes. Advances in molecular genetics have demonstrated that there is not always a clear correlation between molecular genetic and clinical phenotype. Our understanding of genetic mutations is often still at an early stage, with the mutation recognized and characterized, but its pathogenesis unclear. Recognition of the phenotype may indicate correct molecular genetic diagnosis, and unnecessary or premature renaming of conditions may cause confusion. HARP is interesting because acanthocytes may superficially point to a diagnosis of “neuroacanthocytosis”. Further consideration, however, points to a variant of Hallervorden-Spatz disease, as confirmed by demonstrating PANK2 mutations. The extensive time and money usually needed to identify rare point mutations makes the recognition of rare or unusual phenotypes, such as HARP, important. It may be too soon to dismiss the significance of blood lipid abnormalities in these conditions given the availability of detailed lipid electrophoresis and PANK2 sequencing. Further identification of clinical variants of Hallervorden-Spatz syndrome may lead to understanding its pathogenesis, and the role of other modifying genetic and environmental factors. There is additional debate as to whether the spiculed cells commonly called acanthocytes, should more correctly be called echinocytes. [3] We accept the limits of the terms acanthocyte and hypoprebetalipoproteinemia, although we would emphasize that our agarose gels do clearly resolve Lp(a) from beta- and prebeta-lipoproteins (LDL and VLDL) and that our patient lacked a prebeta band confirmed by ultracentrifugation. It is important to recognize the clinical syndrome of HARP, and the memorable and historically illuminating acronym.
Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic 18 February 2004
Adrian Danek, MD, Neurologische Klinik, Ludwig-Maximilians-Universität Postfach 701260, D-81366 München, Germany, Robert A. Hegele, MD, FRCP, FACP Send Correspondence to journal: Re: Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic danek{at}lmu.de Adrian Danek, MD, et al.	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.