Progressive spastic paraplegia as a feature of tetrasomy 18p

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Progressive Spastic Paraplegia as a Feature of Tetrasomy 18p Annalisa Nucaro,1 Ilaria Chillotti,2 Tiziana Pisano,2 Dario Pruna,2 and Carlo Cianchetti2* 1

Istituto di Neurogenetica e Neurofarmacologia, CNR Cittadella Universitaria, Monserrato, Cagliari, Italy


Neuropsichiatria Infantile, Azienda Ospedaliero, Universitaria, Cagliari, Italy

Received 22 February 2010; Accepted 31 May 2010

TO THE EDITOR: The tetrasomy 18p or isochromosome 18p [i(18p)] syndrome is associated with moderate to severe mental retardation, microcephaly, dysmorphic features, and other abnormalities. ‘‘Spasticity’’ or ‘‘hypertonia’’ are frequently reported [about 80% of cases, Swingle et al., 2006], but not clearly defined; such definition is, however, essential in singling out the different nervous structures/pathways involved in the disorder. Here we present a case in which we determined that spasticity was due to a progressive spastic paraparesis, with the involvement of cortico-spinal and afferent somatosensory pathways. The clinical picture of this patient fits the basic features of genetic (or hereditary) spastic paraplegias (GSP), which are due to at least 30 different genetic loci, to date none identified in 18p (http://¼gene&part¼hsp). The propositus was the product of a second pregnancy of unrelated parents. The pregnancy was uncomplicated and the patient was born at 39 weeks of gestation. Apgar score was 8 at the 1st and 10 at the 5th minute. Weight at birth was 2,910 g, length 48 cm, and head circumference 33 cm, all in the range of 1 standard deviation (SD) below the mean. Clinical features during the neonatal period included asymmetric face, hypertelorism, horizontal palpebral fissures, mandibular hypoplasia, low-set ears, hypoplasia of auricles, limited abduction of the hips, right club foot, cryptorchidism, and small scrotum. Poor feeding was apparent within the first few days. At 13 and 23 months, height (respectively, 67 and 80 cm), weight (5 and 7.8 kg), and head circumference (41 and 44 cm) were all considerably below the 2 SD. There was a marked delay in motor (autonomic gait at 5 years) and language (first words at 7 years) milestones. Signs of spastic paraparesis (marked lower limb tendon hyperreflexia with Babinski sign) were first noted at about 4 years. At 13 years the patient has a severe mental retardation (WISC-III: QI < 40; QIV < 40, QIP < 40), without behavioral problems. Physical examination reveals microcephaly (49 cm, significantly below the 2 SD; mean values for age 54 cm), short stature (140.5 cm, 2,5 SD), weight 28.2 kg (1.93 SD). He has spastic paraparesis: bilateral hypertonic adduction of hips with equinovarus feet more severe at left, generalized tendon hyperreflexia and bilateral

Ó 2010 Wiley-Liss, Inc.

How to Cite this Article: Nucaro A, Chillotti I, Pisano T, Pruna D, Cianchetti C. 2010. Progressive spastic paraplegia as a feature of tetrasomy 18p. Am J Med Genet Part A 152A:2173–2175.

Babinski. He walks with tip-toe initial foot contact and slight hip adduction (gait had improved after botulinum toxin injection in the gastrocnemius muscles). Fingers of the hands are also in slight flexor hypertonus and dexterity of hand-finger movement is reduced. Vibratory sensation is preserved. Bladder disturbances are not reported. Dysmorphic features (Fig. 1) included low anterior hair implant, oval facial shape, downslanting palpebral fissures, pointed nasal tip, high nasal bridge, long philtrum, small mouth with protruding lower lip, teeth malocclusion, high palate, low-set small ears, tapering fingers, clinodactyly, camptodactyly, kyphosis, micropenis (3 cm), bilateral cryptorchidism, with normal left and very small right testicle at abdominal ultrasound examination. The cardiac investigation revealed ostium secundum interatrial defect. No other abnormalities of viscera were found. He never had seizures and denied bladder problems. The somato-sensory potentials (SSEPs) evoked by the stimulation of the tibial nerves showed an absence of the cortical response N35 in response to the stimulus at left, and an increased latency (47 msec) at right, with normal lumbar responses bilaterally. Stimulation of median nerves gave normal responses. Brain MRI, EEG, auditory and visual evoked responses were normal.

*Correspondence to: Prof. Carlo Cianchetti, Neuropsichiatria Infantile, Universita, Via Ospedale 119, I-09124 Cagliari, Italy. E-mail: [email protected] Published online 3 August 2010 in Wiley Online Library ( DOI 10.1002/ajmg.a.33576



FIG. 1. Patient’s picture at age 13 years (for details see text). [Color figure can be viewed in the online issue, which is available at]

Chromosome analysis of the propositus and his parents was carried out according to standard protocol and all the 30 QFQ banded metaphases in the patient showed the presence of a supernumerary marker i(18p)[47,XY,i(18)(p10)]. The parents had normal karyotype, indicating a de novo event. FISH analysis, performed according to Li-Star FISH manufacturer’s protocol, using whole specific (Fig. 2a) and sub-telomeric probe (Fig. 2b), confirmed the origin of the marker chromosome. The propositus, in addition to the dysmorphic features with severe intellectual disability consistent with the previously reported cases of i(18p), shows the presence of a progressive spastic paraparesis (lower limbs hypertonus with tendon hyperreflexia and Babinski signs, indicating lesion of the cortico-spinal pathway), with concomitant involvement of the afferent fibers of the dorsal columns of the spinal cord (witnessed by the alterations of the SSEPs). A slight involvement of the cortico-spinal (‘‘pyramidal’’) tract is also suggested for the upper limbs, showing hyperreflexia, slight flexor hypertonus of the fingers, reduced dexterity. As occurs in cases with similar pathology, the longest fibers, like those innervating the lower extremities, are the most affected. In this patient, spastic paraparesis had an early onset (about 4 years of age) and very slow progression.


FIG. 2. (a) FISH with whole specific chromosome 18 painting probe; (b) FISH with sub-telomeric 18p probe. [Color figure can be viewed in the online issue, which is available at]

In the review by Swingle et al. [2006] of 45 cases with i(18p) ‘‘spasticity’’ or ‘‘hypertonia’’ was present in 26/32 (81%) of patients. It is possible that spasticity is not always detectable and may actually be more frequent than reported: for example, due to the excessively young age of the patient studied (since spasticity usually appears at a later age) as in the case of Abeliovich et al. [1993], or due to the co-presence of a 2nd neuron lesion causing hypotonia, as in the cases described by Boyle et al. [2001] (one had meningocele and tethered cord at L4 and the other myelomeningocele). However, none of the cases reported in literature had a description of the neurological features, including no neuro-electrophysiological studies, failing to clearly delineate the neurological pathology in i(18p). Our case shows pathology of both ascending and descending pathways, with a slow progressive course. Therefore, it is a form of progressive spastic paraplegia, with a picture fitting to that of the several forms of GSP, of which more than 30 have thus far been identified, although until now in none of them a location in 18p has been reported. GSPs may be inherited as an autosomal dominant (70–80% of reported families), autosomal recessive or X-linked recessive trait. GSPs are divided into ‘‘pure’’ and ‘‘complex’’ forms. Pure GSPs are characterized by slowly progressive lower limb

NUCARO ET AL. spasticity and weakness, occasionally associated with mild distal loss of vibratory sense or alterations of SSEP. Complex GSPs have additional neurologic or extraneurologic signs or symptoms, including mental retardation, epilepsy, cerebellar ataxia, peripheral neuropathy, optic neuropathy, retinitis pigmentosa, cataracts, and deafness. Only in about half of the GSPs have the genes involved been singled out, and the protein products of the genes play rather different putative roles (e.g., function of the Golgi apparatus, endosomes, axonal transport, axon guidance, myelination, cholesterol/neurosteroid metabolism, protein folding) [Stevanin et al., 2008]. Our case suggests that ‘‘spasticity’’ in the reported cases of i(18p) may be due to a form of GSP. In addition, one or more genes in 18p may be involved in the normal development and wellbeing of motor and sensory pathways. Detailed evaluation and

2175 characterization of the neurological features (including all those reported above) in additional i(18p) patients is recommended.

REFERENCES Abeliovich D, Dagan J, Levy A, Steinberg A, Zlotogora J. 1993. Isochromosome 18p in a mother and her child. Am J Med Genet 46:392–393. Boyle J, Sangha K, Dill F, Robinson WP, Yong SL. 2001. Grand-maternal origin of an isochromosome 18p present in two maternal half-sisters. Am J Med Genet 101:65–69. Stevanin G, Ruberg M, Brice A. 2008. Recent advances in the genetics of spastic paraplegias. Curr Neurol Neurosc Rep 8:198–210. Swingle HM, Ringdahl J, Mraz R, Patil S, Keppler-Noreuil K. 2006. Behavioral management of long-term survivor with tetrasomy 18p. Am J Med Genet Part A 140A:276–280.

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