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• Extension of the SPG26 phenotype in a Spanish family and refinement of its locus on chromosome 12
  Pascale Ribai
  Published on: 7 June 2005

• Published on: 7 June 2005

  Extension of the SPG26 phenotype in a Spanish family and refinement of its locus on chromosome 12

  • Pascale Ribai, MD
  • Other Contributors:
    • Giovanni Stevanin, Sylvie Trefouret, Isabelle Nelson, Caroline Soumphonphakdy, Jean Pouget, Alexandra Durr, Alexis Brice

  Dear Editor,

  Wilkinson et al. reported a Bedouin family in which five out of twelve siblings had a complicated form of autosomal recessive spastic paraplegia. They presented a uniform picture of early onset hereditary spastic paraplegia (HSP) that began at 6-11 years of age with dysarthria, distal wasting of the upper (UL) an...

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  Dear Editor,

  Wilkinson et al. reported a Bedouin family in which five out of twelve siblings had a complicated form of autosomal recessive spastic paraplegia. They presented a uniform picture of early onset hereditary spastic paraplegia (HSP) that began at 6-11 years of age with dysarthria, distal wasting of the upper (UL) and lower limb (LL) muscles and emotional lability. Three affected patients also had intellectual impairment, although it could not be determined whether this resulted from mental retardation or cognitive decline. After exclusion of linkage to the known autosomal recessive HSP loci, a genome-wide scan identified a 22.8 cM region of homozygozity at 12p11.1-12q14 with a maximum lod score of 5.1 that segregated in all affected individuals. This was the first family linked to the locus designated SPG26.

  We report here a new family of Spanish origin (family 112) with a complicated form of autosomal recessive HSP linked to the same locus, that extends the SPG26 phenotype and refines the critical interval on chromosome 12. The parents, who were first cousins, had four children, three of whom were affected. The clinical features are summarized in table 1. Like the family reported by Wilkinson, our patients presented a uniform clinical picture of early onset HSP that began at 8 to 10 years of age, dysarthria, distal UL and LL muscle wasting and mental retardation. In addition, our patients also presented posterior capsule cataracts at birth, peripheral axonal neuropathy, pes cavuswith equinovarus and cerebellar signs including axial instability, limb dysmetria, dysarthria, and horizontal nystagmus. Some patients also had diplopia and altered vestibulo-ocular reflexes.

  The posterior capsule cataracts were assessed by an ophthalmologist. Peripheral neuropathy was confirmed in patients 09 and 10 by electromyography and measurement of nerve conduction velocities. Sensory action potentials were absent in the LL and were greatly reduced in the UL. Sensory and motor nerve conduction velocities were normal. The disability was severe. Patients 10 and 12 were wheelchair-bound at age 54 and 30, respectively, and patient 09 needed two canes to walk at age 45. The father had an unremarkable examination at age 90. The mother, a year before she died at 88, had increased reflexes in the LL and bilateral extensor plantar reflexes, in the absence of gait abnormality, cataracts or mental retardation. She was therefore considered unaffected. The unaffected sister had normal clinical examination at age 54.

  Intellectual impairment in our patients was noted early and was not progressive, suggesting mental retardation rather than cognitive deterioration. The intellectual status of patient 09 was evaluated at age 45. He had a low IQ (72), left school at age 20 and worked in a centre for the disabled. Patient 12 never went to school because of learning difficulties. In patients 09 and 10, brain magnetic resonance imaging (MRI) showed cortical atrophy that was unusual for their age (45 and 52). The cerebellum was normal.

  After excluding mutations in the coding exons of the SPG7 gene and linkage to known autosomal recessive HSP loci, we performed a genome-wide scan with 400 microsatellite markers spaced approximately every 10cM using standard procedures. Positive multipoint lod score values (Z>1), calculated with the ALLEGRO software (DECODE Genetics), were obtained for only 3 chromosomal regions. Twenty-eight additional markers were used to explore these regions, two of which were excluded on the basis of haplotype reconstruction and lod score values below the threshold of –2 (data not shown). A maximal multipoint lod score of 2.53 was reached, however, in a 30cM region flanked by markers D12S1617 and D12S1702. The minimal region of homozygosity shared by the affected patients was defined by two recombination events that occurred between markers D12S1617 and D12S345 in patient 12 and between D12S1585 and D12S1686 in the unaffected sib (individual 11). This region overlapped with the SPG26 candidate interval, reducing it from 23 to 20 cM (figure not shown).

  In conclusion, this second family putatively linked to SPG26 extends the clinical phenotype of this complex form of HSP and refines the critical region. There are more than 200 identified genes in this interval. More families are therefore needed to further refine the locus and identify the responsible gene.

  Acknowledgments:
  

  The authors are grateful to Drs Sylvie Forlani and Merle Ruberg for their help as well as the DNA and cell Bank of IFR-70 and the Centre National de Genotypage (Evry) for their help. PR was supported by a fellowship from the European Neurological Society and the Collège de Médecine des Hôpitaux de Paris. This work was funded by the Verum Foundation (to AB) and the GIS-Rare Diseases Institute (to AD and GS).

  Pascale RIBAI, MD,^1,2 Giovanni STEVANIN, PhD,^1,2 Sylvie TREFOURET, MD,⁵ Isabelle NELSON, PhD,¹ Caroline SOUMPHONPHAKDY, MS,¹ Jean POUGET, MD,⁵Alexandra DURR, MD, PhD,^1,2 Alexis BRICE, MD.^1,2,3,4

  ¹INSERM U679 (former U289) Federative Institute for Neuroscience Research (IFR70), Salpêtrière Hospital, Paris, France; ²Department of Genetics Cytogenetics and Embryology, AP-HP, Salpêtrière Hospital, Paris, France, ³Federation of Neurology, AP-HP, Salpêtrière Hospital, Paris, France, ⁴Salpêtrière Medical School, Pierre and Marie Curie University, Paris, France, ⁵Department of Neurology and Neuromuscular Diseases, La Timone Hospital, Marseille, France.

  Address correspondence to Pr Alexis Brice, INSERM U679 (former U289), Hôpital de la Salpêtrière, 47 Bd de l’Hôpital, 75013 Paris, France. E-mail: brice{at}ccr.jussieu.fr

  References
  1. Wilkinson PA, Simpson MA, Bastaki L et al. A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14. J Med Genet (2005),42:80-2.

  Table 1. Clinical features of the three members of family 112 with a complicated form of AR-HSP linked to the SPG26 locus.

  Patients	09	10	12
  Age at examination (y)	45	52	67
  Onset (y)	8	8	10
  Cerebellar signs	Dysarthria, axial and UL ataxia.	Dysarthria, nystagmus, hypermetric ocular saccades, axial ataxia	Dysarthria, axial ataxia
  UL muscle wasting	-	+	-
  LL muscle wasting	+	+	+
  LL brisk reflexes	+	+	-
  UL brisk reflexes	-	-	-
  Extensor plantar reflexes	+	+	+
  Congenital posterior capsular cataracts	+	+	+
  Pes cavus and equinovarus	+	+	NA
  Peripheral neuropathy	+	+	NA
  Decreased vibration sense	+	+	+
  IQ	72	low (not determined)	very low (not determined)
  Cerebral MRI	Bilateral temporal atrophy	Bilateral frontal and temporalatrophy
  Additional signs	Diplopia, altered VOR	Absent reflexes at ankle, sphincter disturbances	Sphincter disturbances, abolished myotatic reflexes in the LL, diplopia

  +: Presence of the corresponding sign, -: Absence of the corresponding sign, NA: Not available, UL: Upper limbs, LL: Lower limbs, VOR: Vestibulo-ocular reflex.

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  Conflict of Interest:
  None declared.

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