A clinical study of a large inbred kindred with pure familial spastic paraplegia

A clinical study of a large inbred kindred with pure familial spastic paraplegia

Brain & Development 21 (1999) 478±482 www.elsevier.com/locate/braindev A clinical study of a large inbred kindred with pure familial spastic parapleg...

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Brain & Development 21 (1999) 478±482 www.elsevier.com/locate/braindev

A clinical study of a large inbred kindred with pure familial spastic paraplegia Hatem E. El-Shanti a,*, Azhar S. Daoud b, Anwar Batieha c a

Departments of Pediatrics and Medical Genetics, School of Medicine, Jordan University of Science and Technology, Irbid, Jordan Departments of Pediatrics and Child Neurology, School of Medicine, Jordan University of Science and Technology, Irbid, Jordan c Department of Public Health and Community Medicine, School of Medicine, Jordan University of Science and Technology, Irbid, Jordan b

Received 10 December 1998; received in revised form 8 April 1999; accepted 28 May 1999

Abstract Background and objectives: Spastic paraplegia, an uncommon neurodegenerative disorder with phenotypic and genotypic heterogeneity, is mainly characterized by progressive weakness and spasticity of the lower limbs. We here present a large inbred family with pure familial spastic paraplegia outlining the clinical picture, the age at onset and the possible mode of inheritance. Methods: This family was ascertained through two probands after which we structured an extended 10 generation pedigree. We examined 43 available family members to identify affected individuals based on ®xed criteria. The clinical presentation and phenotypic speci®cs of this disease were studied in the affected members. We analyzed the possible mode of inheritance and the age at onset in this family. Results: This 10 generation family reported about 50 affected individuals distributed over 5 consecutive generations. We identi®ed 13 affected individuals out of the examined 43 and ®ve individuals were classi®ed as probably affected. We noticed the clinical speci®cs of this disorder in this family and identi®ed some unique features not described in previous reports. Discussion and conclusion: The mode of inheritance is either autosomal recessive or autosomal dominant with incomplete penetrance or variable expression of the age at onset. The age at onset seems to decrease with successive generations, either due to a true anticipatory phenomenon or to increased awareness. The unique features of this disorder in this family are discussed. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Spastic; Paraplegia; Pseudohypertrophy

1. Introduction Familial spastic paraplegia (FSP) is a rather uncommon neurological disorder that shows considerable phenotypic and genotypic heterogeneity [1]. The condition is characterized by progressive weakness and spasticity of the lower limbs with little or no involvement of the upper extremities [2±4]. The predominant neuropathological lesion is loss of myelin and axons in the lateral corticospinal (pyramidal) tracts [5]. There is sometimes involvement of gracile and cuneate tracts and rarely the spinocerebellar and anterior corticospinal tracts [5]. Although it was ®rst described by Strumpell in 1880, a similar description 4 years earlier is documented [6,7]. Due to its heredofamilial nature, it is termed familial and sometimes hereditary spastic paraplegia [4]. Several classi®cations have been proposed based on the pattern of inheritance, the age at onset and the clinical * Corresponding author. Hatem E. El-Shanti, PO Box 3211, Irbid, 21110 Jordan. Tel.: 1962-2-295111 ext. 3775; fax: 1962-2-7278119. E-mail address: [email protected] (H.E. El-Shanti)

features [8]. It is agreed upon that there are pure and complicated forms. Complicated forms have added features of cutaneous lesions, mental retardation, peripheral neuropathy, distal amyotrophy, retinal changes or ataxia and are mostly autosomal recessive. The pure forms are autosomal dominant, autosomal recessive or rarely X-linked and are more common than the complicated forms [9,10]. The pure autosomal dominant form is more common than the pure autosomal recessive. The range of age at onset is wide but seems to be concordant within families [9]. A recent study shows that the age of onset of symptoms is a poor criterion for classifying autosomal dominant spastic paraplegias [11]. The presence of a huge number of different clinical reports and comprehensive studies is a re¯ection of the profound phenotypic heterogeneity of the disorder [1]. Linkage analysis studies on the autosomal forms of pure spastic paraplegia provide evidence for the genotypic heterogeneity of the disorder. Three forms with autosomal dominant linkage (FSPI ˆ SPG3; FSP2 ˆ SPG4; F5P3 ˆ SPG6) and two forms with autosomal recessive linkage (SPG5A; SPG5B) are recognized [11±15]. Out of the domi-

0387-7604/99/$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(99)0005 7-1

H.E. El-Shanti et al. / Brain & Development 21 (1999) 478±482

nant forms, FSP2/SPG4 shows striking intra and interfamilial variation in age of onset of symptoms, rate of disease progression and severity, with some reports of anticipation [11,16±18]. The autosomal recessive families show narrower variation in the clinical picture despite the demonstration of genotypic heterogeneity [15,19]. We here describe the clinical features of a large multigeneration inbred family with pure familial spastic paraplegia. This family shows unique clinical features of the disorder con®rming the phenotypic heterogeneity. We also discuss the possible modes of inheritance of the disorder in this family.

2. Patients, materials and methods The family was identi®ed through two different probands (VII-9 and V-8) ascertained during a study conducted at Jordan University of Science and Technology aiming at estimating the prevalence of neurogenetic disorders in Northern Jordan. The two probands were thoroughly investigated with head and spine CT and MRI, electromyograms (EMG), nerve conduction studies (NCS) and CPK serum levels before reaching the ®nal diagnosis. We obtained data from several key family members to construct the pedigree which goes back about 10 generations [20]. Forty-three individuals were questioned and examined by a neurologist during a period of 6 months. These individuals were chosen randomly, but also based on their availability for examination. The history included direct questioning about gait changes including tip-toe walking, frequent falls, dif®culty with stairs, hearing dif®culties and sphincter dysfunction symptoms. The neurological examination included gait, tone, muscle power, deep tendon re¯exes, super®cial re¯exes, muscle bulk and super®cial and deep sensory bedside evaluation. The examination was carried out on both upper and lower extremities. Also, lower extremity functions were assessed by examining hopping, toe and heel walking. Careful skin examination was performed for every individual examined, while ophthalmologic examination was done only for affected individuals. The diagnosis in family members was made if there were two or more of the following criteria. 1. Symptoms of spasticity (tip toe walking, shuf¯ing gait, etc.) 2. Hyperre¯exia of the lower extremities. 3. Sustained ankle or knee clonus or both. 4. Signs of spasticity (hypertonia) and weakness. 5. Extensor plantar response (Babinski sign). Although, in the presence of positive family history the presence of one criterion of pyramidal involvement might be enough to make the diagnosis, we elected to have at least two criteria for the de®nitive diagnosis.

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Three patients, V-8, V-14 and VII-9 had somatosensory evoked potentials done. 3. Case reports 3.1. First proband VII-9 at the time of evaluation was a 14-year-old male who presented with tip-toe walking that became noticeable during the ®rst year. Otherwise, he was healthy and active. He did not complain of frequent falling down, dif®culty with stairs, hearing dif®culty or urinary sphincteric symptoms. On physical examination, his gait was that of a tip-toe walker without ataxia. He had normal muscle power and tone all over and intact cranial nerves. The deep tendon re¯exes were normal in the upper limbs but exaggerated in the lower limbs with sustained ankle clonus. The plantar re¯ex was down going bilaterally. Hopping and heel-walking were performed with dif®culty. Signs denoting involvement of the cerebellum and the extrapyramidal tracts were absent. Proprioception and vibration sense in the lower limbs were intact. Ophthalmologic examination was normal without evidence of optic nerve atrophy or abnormal retinal pigmentation. There were no cutaneous lesions and his school performance was satisfactory. The serum CPK was normal on two occasions, as well as serum calcium, phosphorus, sodium, potassium and magnesium. The head and spine CT and MRI were reported as normal. Both the EMG and the NCS were reported as normal. Speci®cally, somatosensory evoked potential for the posterior tibial nerve was reported as having normal latency and amplitude with respect to age. 3.2. Second proband V-8 at the time of evaluation was a 60-year-old male who noticed a change in his gait (shuf¯ing) in his late twenties. He complained of dif®culty with stairs. He did not have any hearing dif®culty or urinary sphincteric symptoms. On physical examination, he walked with dif®culty without ataxia. Currently (3 years later), he is wheel-chair-bound. He had normal muscle power and tone in the upper limbs but markedly reduced power and marked hypertonia in the lower limbs. The deep tendon re¯exes were normal in the upper limbs but exaggerated in the lower limbs with sustained ankle and knee clonus. The plantar re¯ex was up going bilaterally. Signs denoting involvement of the cerebellum and the extrapyramidal tracts were absent. Proprioception and vibration sense in the lower limbs were intact. Ophthalmologic examination was normal without evidence of optic nerve atrophy or abnormal retinal pigmentation. There were no cutaneous lesions. Pseudohypertrophy of the calf muscles was noticed during the examination which made us denote this observation and look for it when examining the remainder of the family members. The serum CPK was normal, as well as serum calcium,

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H.E. El-Shanti et al. / Brain & Development 21 (1999) 478±482

Fig. 1. A subset of the pedigree of the family. Blackened symbols denote affected individuals either by examination or by history. Striped symbols denote probably affected individuals either by examination or by history. Examined individuals are marked with a bar over the symbol. Notice the extensive number of consanguinity loops.

phosphorus, sodium, potassium and magnesium. The head and spine CT and MRI were reported as normal. Both the EMG and the NCS were reported as normal. Speci®cally, somatosensory evoked potential for the posterior tibial nerve was reported as having normal latency and amplitude with respect to age.

4. Results The pedigree information collected from key family members goes back 10 generations and includes about 240 individuals of whom about 50 are affected. Fig. 1 shows a subset of the pedigree of the family including only the examined individuals. We could not include the extended pedigree due to the space and the complicated consanguinity loops present. Other than the examined individuals, the affected status of the remainder of the affecteds was determined from the observations of family members.

Out of 43 examined individuals (24 males, 19 females) 27 were unaffected, 13 (nine males, four females) were affected and in ®ve a clinical conclusion could not be reached. All 13 clinically affected individuals were symptomatic. Although four patients (age 14±22 years) did not report symptoms themselves, symptoms were reported by their parents, mainly in the form of abnormal gait. These four patients had two criteria for the diagnosis other than the symptoms. The details of the clinical picture is shown in Table 1. The family members reported that a decrease in the age at onset is noticeable with successive generations. None of the affected individuals had sensory involvement by bedside assessment (vibration sense and proprioception), urinary symptoms or upper extremity symptoms or signs. Extensor plantar response was present in older patients, while clonus was present in everyone. Nine of the affected individuals showed increased muscle bulk of the calf (pseudohypertrophy). All 13 affected individuals had at least three criteria at examination, which made the diagnosis quite clear. Five patients (age 5±9 years) were reported by their

Table 1 The clinical picture of the thirteen examined affected indiviuals a

VII-8 VII-9 V-8 VII-4 V-6 VI-9 VI-10 V-14 VII-2 V-12 VI-24 V-2 VI-6 a

Sex Age at examination Presenting symptom Age at onset

LE tone LE power DTRs

Clonus

Plantar re¯ex Increase in muscle bulk

F M M F F M M M M F M M M

Normal Normal Hyper Normal Normal Hyper Hyper Hyper Normal Normal Hyper Hyper Normal

Present Present Present Present Present Present Present Present Present Present Present Absent Present

Down Down Up Down Equivocal Down Down Up Down Down Up Up Down

17 14 60 23 52 26 14 58 6 22 43 55 20

None Tip-toe walk Shuf¯ing gait Gait change Shuf¯ing gait Gait change None Shuf¯ing gait Tip-toe walk None Tip-toewalk Tip-toewalk None

NA 13 27 15 32 6 NA 20 6 NA 14 20 NA

5 5 2 4 4 4 5 2 5 5 4 3 5

Hyper Hyper Hyper Hyper Hyper Hyper Hyper Hyper Hyper Hyper Hyper Hyper Hyper

No Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes

The presenting symptom is what was reported by the individual. F: Female. M: Male. LE: Lower extremity. DTR: Deep tendon re¯ex.

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parents to have gait change in the form of slight intoeing. In the ®ve patients hyperre¯exia of the lower extremities was the only ®nding on examination. These ®ve patients were classi®ed as probably affected since each had only one diagnostic criterion. The remainder of examined individuals were completely normal with no symptoms, normal lower limb power and tone, normal deep tendon and plantar re¯exes and 110 clonus. The calf muscles in unaffected individuals were of normal bulk. 5. Discussion The mode of inheritance of this condition in this family is uncertain at this stage of the study. Autosomal recessive mode of inheritance is supported by the extensive inbreeding with multiple consanguineous loops in the pedigree and that several consanguineous healthy parents have affected offspring. For example, V-6 and VI-22 have two affected offspring and are both normal at the age of 50 and 44 years respectively and remain normal 3 years later. Also, consanguinity is documented in all affected individuals with affected offspring, such as V-2, V-9, V-14 and V-19 (V9's marriage is not shown in the pedigree). However, an autosomal dominant model ®ts this family as well. In that instance incomplete penetrance or variable expressivity in age at onset, such as that noticed in FSP2, can explain the affected individuals with normal parents. Also, the lack of systematic ascertainment of affected individuals due to social reasons may account for undiagnosed individuals in the pedigree. The anticipation, which is suspected in this family conforms with an autosomal dominant condition. The onset of symptoms in affected family members seems to be earlier in younger generations than in the older. For example V-8 presented with gait change in his late twenties, while his daughter, VII-4, presented with noticeable symptoms at the age of 15 years. Individual V-9 was about 62 years at evaluation (refused to be examined) reported onset of symptoms in late twenties but recognized symptoms in his two affected sons, VI-9 and VI-10, around the age of 6 years. Another example, is V-14 who presented at the age of 20 years but noticed gait change in his daughter,VI-12, at the age of 10 years and in his grandson, VII-2, as early as 6 years. An anticipatory phenomenon is only probable if the disease is autosomal dominant in this family. However, this still could be an autosomal recessive condition and the increased awareness of this disease among family members can be the explanation of this phenomenon. The male to female ratio among affected individuals is 9 to 4. This skewed ratio is probably due to two reasons; ®rst, some affected young females avoided being examined and were not introduced to the examiner; second, more males were examined (male to female ratio among examined is 24 to 19). This was anticipated due to social and cultural reasons.

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The clinical picture in this family has certain unique features distinguishing it from previous reports. First, the disease is purely motor without any sensory involvement even in the older patients. There are no urinary symptoms in any of our examined patients. Second, there is no involvement of the upper limbs even in older patients with advanced disease. Third, the plantar re¯ex is normal in patients with a short course of the disease, while an extensor response becomes obvious in older patients with a longer course. On the other hand, ankle clonus is present in all affected individuals, with the exception of one who has a prolapsed intervertebral disc and a multitude of neurological symptoms related to that problem. Fourth, nine out of thirteen affected individuals have an increase in the calf muscle bulk similar to the pseudohypertrophy seen in Duchenne muscular dystrophy. This previously undescribed ®nding is being thoroughly studied to see if it helps with early suspicion or diagnosis. Acknowledgements This work is supported by grant 21/96 from the Deanship of Scienti®c Research, Jordan University of Science and Technology, Irbid, Jordan. We speci®cally acknowledge the help of Dr. Omar Sartawi, the neurophysiologist at JUST, who skillfully performed the somatosensory evoked potentials. References [1] On-line Mendelian Inheritance in Man, OMIM [TM]. Johns Hopkins University, Baltimore, MD. MIM Number: {182600}: {10/19/1994}: World Wide Web URL: http://www3.ncbi.nlm.nih.govlomim/ [2] Holmes CJL, Shaywitz BA. Strumpell's pure familial spastic paraplegia: Case study and review of the literature. J Neurol Neurosurg Psychiatry 1977;40:1003±1008. [3] Boustany R-MN, Fleischnick E, Alper CA, Marazita ML, Spence MA, Martin JB, Kolodny EH. The autosomal dominant form of `pure' familial spastic paraplegia: Clinical ®ndings and linkage analysis of a large pedigree. Neurology 1987;37:910±915. [4] Harding AL. Hereditary spastic paraplegia. Semin Neurol 1993;13:333±336. [5] Behan WMH, Maia M. Strumpell's familial spastic paraplegia: Genetics and neuropathology. J Neurol Neurosurg Psychiatry 1974;37:8±20. [6] Strumpell A. Beitrage zur pathologic des ruckenmarks. Arch Psychiat Nervenker 1880;10:676±717. [7] Seeligmueller A. Sklerose der seitenstrange des ruckenmards bei vier kindern derselben gamilie. Dtsch Med Wochenschr 1876;2:185±186. [8] Harding AL. Classi®cation of the hereditary ataxias and paraplegias. Lancet 1983;1:1151±1155. [9] Harding AL. Hereditary `pure' spastic paraplegia: a clinical and genetic study of 22 families. J Neurol Neurosurg Psychiatry 1981;44:871±883. [10] Keppen LD, Leppert MF, O'Connell P, Nakamura Y, Stauffer D, Lathrop M, et al. Etiological heterogeneity in X-linked spastic paraplegia. Am J Hum Genet 1987;41:933±943. [11] Hazan J, Fontaine B, Bruyn RPM, Lamy C, van Deutekom JCT, Rime CS, et al. Linkage of a new locus for autosomal dominant familial

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