Neuropediatrics 2015; 46 - FV02-03
DOI: 10.1055/s-0035-1550651

Mutation Spectrum and Infantile Manifestation in Hereditary Spastic Paraplegia

S. Schirmer 1, W. Wittmann 2, U. Schulte-Mattler 2, Z. Kohl 3, U. Hehr 4
  • 1Zentrum für Humangenetik, Regensburg, Germany
  • 2Kinderzentrum St. Martin Regensburg, Regensburg, Germany
  • 3Abtl. für Molekulare Neurologie, Universitätsklinikum Erlangen, Erlangen, Germany
  • 4Zentrum für Humangenetik, Institut für Humangenetik Universität Regensburg, Regensburg, Germany

Aims: Hereditary spastic paraplegia (HSP) is genetically heterogeneous and clinically characterized by gait impairment because of weakness and spasticity of the lower limbs. In Caucasian populations, heterozygous Spastin mutations account for the majority of patients (SPG4) with predominant clinical manifestation within the third or fourth decade of life. A clinical manifestation during childhood is well known, but more common in less frequent forms such as SPG3a or complicated HSP, for example, SPG11.

Methods: An individual genetic testing strategy based on clinical and family data by Sanger Sequencing and MLPA for 240 index patients. Neuropediatric or neurological assessment and/or evaluation of available medical records.

Results: In our HSP cohort, causal mutations were identified in 58 families (24%). Most frequently, Spastin mutations were observed in 44 independent index patients at an average age of 50 years. In more detail, we report the clinical findings in three patients with infantile onset from two SPG4 families because of heterozygous Spastin mutations. The first offspring of a 33-year-old heterozygous asymptomatic female mutation carrier in a large pedigree with late-onset in addition to the maternally inherited Spastin mutation c.911delC carried the previously described Spastin modifier p.Ser44Leu on her paternal allele. The HSP diagnosis for the second girl was suspected at the age of 21 months because of an abnormal gait in herself and her mother, both are heterozygous for the nonsense mutation p.Arg562*. Her mother at the age of 35 years presented with mild, but characteristic spasticity of the lower limbs with pyramidal signs. She had obtained supportive physiotherapy and leg braces because of delayed and toe-walking, which in the absence of any obvious progression had always been considered to be nongenetic.

Conclusion: Infantile HSP because of mutations in Spastin or other associated genes may initially present as delayed and toe-walking and nonprogression over several decades similar to spastic diplegic cerebral palsy.

Keywords: hereditary spastic paraplegia, infantile, spastin mutation.