LETTER TO THE EDITOR Further evidence that DDHD2 gene mutations cause autosomal recessive hereditary spastic paraplegia with thin corpus callosum A. Magariello a, *, L. Citrigno a, *, S. Zuch- ner b , M. Gonzalez b , A. Patitucci a , V. Sofia c , F. L. Conforti a , I. Pappalardo c , R. Mazzei a , C. Ungaro a , M. Zappia c and M. Muglia a a Institute of Neurological Sciences, National Research Council, Mangone (CS), Italy; b Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medi- cine, University of Miami, Miami, FL, USA; and c Dipartimento G.F. Ingrassia Sezione di Neuroscienze Universit  a di Ca- tania, Catania, Italy Correspondence: M. Muglia, Institute of Neurological Sciences, National Research Council, 87050 Mangone (Cosenza), Italy (tel.: +39 0984 9801 228; fax: +39 098 496 9306; e-mail: m.muglia@isn.cnr.it). Received: 22 July 2013 Accepted: 16 October 2013 Autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callo- sum (ARHSP-TCC) is a common form of complex HSP, representing about one- third of the autosomal recessive forms [1]. DDHD2 gene mutations have recently been identified in the SPG54 locus and are responsible for ARHSP- TCC with intellectual disability, develop- mental delay and onset in childhood [2,3]. Until now, only six families (two Iranian, one Indian, one Canadian, one Dutch-Filippino and one Omani) were described as having DDHD2 mutations. In the current study, we report two Ital- ian brothers with ARHSP-TCC due to two deleterious compound heterozygous missense mutations that have been identi- fied in the DDHD2 gene by exome sequencing. The patients were two siblings from an Italian family without consanguinity (Fig. 1a). They were born at term and had no neonatal problems. Initial signs of intellectual disability were apparent by the age of 4–5 years, with learning diffi- culties at school. Over the subsequent years they began to complain of gait disturbances with progressive worsening during the last few years. The elder brother (II:1) is currently 47 years old. At the time of our visit he was 40 years old. Neurological examina- tion at that time disclosed pyramidal tract signs with spastic paraplegia, hyper- reflexia, weakness of the right upper limb, bilateral Hoffman and Babinski signs and bilateral palmomental reflex. Hypopallesthesia in the upper and lower limbs and sensorimotor polyneuropathy were also evident. Furthermore, the elder brother showed intellectual disability with an IQ of 43, microcephaly and bilateral pes cavus. The younger brother (II:2) is currently 46 years old. At the time of our visit he was 39 years old. Neurological examina- tion disclosed bilateral nystagmus in lat- eral gaze, spastic paraplegia, hyperreflexia, weakness of the right upper limb, bilateral Hoffman and Ba- binski signs and bilateral palmomental reflex. He also had intellectual disability with an IQ of 44. Brain magnetic resonance imaging (MRI) in both sib- lings showed severe thinning of the cor- pus callosum. Moderate leukoencephalopathy with cortical, cere- (a) (d) (b) (c) Figure 1 (a) Pedigree of the family with the mutations segregation. Exome sequencing and MRI have been performed in the patient (II:2) indicated by the arrow. (b) Midsag- ittal T1-weighted MRI of the brain shows a marked thin corpus callosum. (c) Trans- verse FLAIR-weighted MRI of the brain shows subtle white matter hyperintensities. (d) Sequence chromatograms show the Sanger confirmation of the two compound DDHD2 mutations. *These two authors contributed equally to the manuscript. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS e25 European Journal of Neurology 2014, 21: e25–e26 doi:10.1111/ene.12305