LETTER TO JMG

A new locus for autosomal recessive complicated hereditary
spastic paraplegia (SPG26) maps to chromosome
12p11.1–12q14
P A Wilkinson, M A Simpson, L Bastaki, H Patel, J A Reed, K Kalidas, E Samilchuk, R Khan,
T T Warner, A H Crosby
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

J Med Genet 2005;42:80–82. doi: 10.1136/jmg.2004.020172

T
he term hereditary spastic paraplegia (HSP) is used to
describe a group of clinically and genetically hetero-
geneous disorders in which the defining clinical feature

is progressive spasticity and weakness of the lower limbs. The
phenotype is traditionally classified as ‘‘pure’’ when symp-
toms and signs are generally confined to those of a
progressive spastic paraparesis, or ‘‘complicated’’ when
associated with additional neurological or other clinical
features.1 Inheritance may be autosomal dominant, auto-
somal recessive, or rarely X linked. Overall autosomal
dominant inheritance is most commonly associated with
pure forms of the disease, whereas autosomal recessive HSP
shows greater phenotypic variability, including several well
defined syndromes.2 3

To date nine autosomal recessive HSP loci have been
identified and causative mutations found in three genes:
SPG7 (paraplegin), SPG20 (spartin), and SPG21 (maspar-
din). SPG7 encodes paraplegin, a mitochondrial protein,
which is a member of the AAA protein superfamily (ATPase
associated with diverse cellular activities) and is homologous
to a number of yeast mitochondrial metalloproteases.4 SPG7
mutations may result in either pure or complicated HSP
phenotypes.4 5 Muscle biopsy analysis of patients with SPG7
mutations may show histological evidence of mitochondrial
dysfunction4 6 and recently biochemical studies have shown
specific defects in mitochondrial respiratory chain function.5 7

Mutations in the SPG20 and SPG21 genes have so far only
been identified in the Old Order Amish population in
association with well characterised complicated HSP pheno-
types.8 9 Spartin, the protein product of SPG20 mutated in
Troyer syndrome, contains a MIT domain that is found
almost exclusively in molecules thought to play a role in
subcellular trafficking.8 10 Only one study has so far been
published relating to the function of maspardin—the protein
product of the SPG21 gene mutated in Mast syndrome. This
suggests co-localisation with transportation vesicles and
implies a role in protein transportation or sorting.9 11

In the current study we have ascertained a large
consanguineous family comprising five affected and seven
unaffected siblings in which the parents were first cousins of
Bedouin ancestry.12 A uniform early onset of disease at
between seven and eight years of age was noted. At the time
of examination all affected individuals had signs of a
progressive spastic paraparesis with dysarthria and distal
amyotrophy in both upper and lower limbs. The three eldest
affected subjects were also felt to have a degree of intellectual
impairment (table 1) with reduced IQ, although it is unclear
whether this represents progressive cognitive decline.
Neurological examination of the parents and the remaining
siblings was unremarkable. Routine biochemical studies
and neurophysiological testing including nerve conduction

velocities and EEG were normal. The appearances on
magnetic resonance imaging were normal.
Linkage to the previously described autosomal recessive

HSP loci was excluded using polymorphic microsatellite
markers spanning these regions (data not shown). Genome-
wide linkage analysis, using parents and affected individuals
only, was carried out with the ABI linkage marker set
(version 2.5) with an ABI 3100 genetic analyser and
Genotyper software (version 3.7).
A single region of homozygosity was identified on

chromosome 12 flanked by markers D12S345 and D12S326.
Marker saturation analysis demonstrated a 22.8 cM region of
homozygosity co-segregating with the disease in all affected
individuals flanked by markers D12S59 and D12S1676 (fig 1).
Multipoint LOD scores across the region—calculated using
GENEHUNTER (version 2.1) under the assumption of equal
allele frequencies and equal male and female recombination
rates, with the disease modelled as an autosomal recessive
trait with complete penetrance (allele frequency 10

24
)—were

significantly positive, with a maximum score of 5.1 between
markers D12S1686 and D12S1702 (fig 2). A database search
of the critical interval identified approximately 300 known or
predicted genes including KIF5A, in which a missense
mutation (A767G) has previously been reported in a family
with an uncomplicated autosomal dominant form of HSP.13

Direct sequencing of all 28 exons and splice junctions of the
KIF5A gene, as previously described,13 in parents and affected
individuals did not reveal any pathogenic mutations.

Key points

N The hereditary spastic paraplegias (HSPs) are a
genetically and clinically heterogeneous group of
neurodegenerative disorders.

N A genome-wide screen was carried out in a con-
sanguineous Kuwaiti family with autosomal recessive
HSP complicated by dysarthria, distal amyotrophy,
and mild intellectual impairment in some affected
individuals.

N This defined a single region of homozygosity co-
segregating with the disease spanning 22.8 cM of
chromosome 12p11.1–12q14, flanked by markers
D12S59 and D12S1676 (multipoint LOD score = 5.1).

N This HSP neuropathy represents a novel genetic entity
designated SPG26.

Abbreviations: HSP, hereditary spastic paraplegia

80

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However, we cannot exclude the possibility of an intronic
mutation or a mutation in a distant regulatory sequence.

COMMENT
Using this consanguineous Kuwaiti family we have identified
a novel locus for autosomal recessive complicated HSP to a
22.8 cM region on chromosome 12. Although this region
contains the KIF5A gene, the fact that no pathogenic
mutations were identified in affected individuals in any of
the exons and flanking splice junctions in this pedigree is
strongly supportive of a further causative gene in this region.
The different mode of inheritance and different phenotype
compared with that of KIF5A offers further support of this
hypothesis. This study should prompt the investigation of
additional autosomal recessive HSP families for linkage to
this region on chromosome 12, which may aid in the
refinement of this currently large locus. Based upon the
proposed functions of the genes so far identified in the
various forms of HSP, various different underlying patho-
genic mechanisms have been proposed, including the
disrupted development of the corticospinal tracts, mitochon-
drial dysfunction, and defects in subcellular transportation
and sorting processes.14–16 The ultimate identification of the
SPG26 causative gene will further elucidate the pathogenesis

Table 1 Clinical features

Feature

Affected family member

1 2 3 4 5

Age at examination (years) 42 39 36 30 22
Onset 6 years 6 years 6 years 6 years 11 years
Dysarthria +++ +++ +++ +++ 2
Tongue tremors + + + + +
Atrophy of small hand muscles +++ + +++ +++ +++
Muscle tone Spastic LL Spastic LL Spastic LL Spastic LL Slightly spastic LL
Knee reflex +++ +++ +++ +++ 2
Clonus +++ + + 2 2
Extensor plantar response +++ +++ +++ 2 2
Gait Spastic ataxic Spastic Spastic Spastic Spastic
Emotional lability + +++ + +++
IQ Total 55 Total 61 Total 54 Total 56 Total 68

Verbal 55 Verbal 55 Verbal 52 Verbal 48 Verbal 73
Performance 61 Performance 72 Performance 73 Performance 73 Performance 64

The case numbers 1–5 correspond to the affected cases from left to right in fig 1 below.
Findings are graded by relative severity: 2absent; +mild; ++moderate; +++severe.
IQ, Wechsler adult intelligence scale; LL, lower limb.

Figure 1 Pedigree of the Kuwaiti family used to map the SPG26 locus, showing haplotypes across the interval.

Figure 2 Multipoint LOD scores for markers situated across the SPG26
locus, flanked by markers D12S59 and D12S1676, producing a peak
score of 5.1.

The SPG26 locus 81

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of this form of HSP and improve our understanding of the
mechanisms of neurodegeneration in this heterogeneous
disease.

ACKNOWLEDGEMENTS
We are grateful to all the patients and their relatives who participated
in this study. This work was supported by grants from Action Medical
Research UK, the Birth Defects Foundation (UK), and The Wellcome
Trust. The work was carried out within the network of the London
Ideas Knowledge Park.

Authors’ affiliations
. . . . . . . . . . . . . . . . . . . . .

P A Wilkinson, M A Simpson, H Patel, J A Reed, K Kalidas, A H Crosby,
Department of Medical Genetics, St George’s Hospital Medical School,
London SW17, UK
P A Wilkinson, T T Warner, Department of Clinical Neurosciences,
Royal Free and University College Medical School, London NW3, UK
L Bastaki, E Samilchuk, R Khan, Kuwait Medical Genetics Centre,
Maternity Hospital, Kuwait

Competing interests: none declared

Correspondence to: Dr Andrew H Crosby, Department of Medical
Genetics, St George’s Hospital Medical School, Cranmer Terrace,
London SW17 0RE, UK; acrosby@sghms.ac.uk

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