Thin corpus callosum and amyotrophy in spastic paraplegia—Case report and review of literature

Clinical Neurology and Neurosurgery 108 (2006) 692–698

Case report

Thin corpus callosum and amyotrophy in spastic paraplegia—Case report and review of literature Beate Winner a,∗ , Claudia Gross b , G¨okhan Uyanik a , Wilhelm Schulte-Mattler a , Ralf L¨urding a , J¨org Marienhagen c , Ulrich Bogdahn a , Christian Windpassinger d , Ute Hehr b , J¨urgen Winkler a,∗ a

b

Department of Neurology, University of Regensburg, Regensburg, Germany Center for Gynecologic Endocrinology, Reproduction Medicine and Human Genetics, Regensburg, Germany c Department of Nuclear Medicine, University of Regensburg, Regensburg, Germany d Institute of Medical Biology and Human Genetics, University of Graz, Graz, Austria Received 15 March 2005; received in revised form 13 June 2005; accepted 13 June 2005

Abstract We report the clinical, structural, functional and genetic characterization of a 37-year-old Caucasian female, presenting as a sporadic case of complicated spastic paraplegia with thin corpus callosum (CC), cognitive impairment, amyotrophy of the hand muscles and a sensorimotor neuropathy and review the literature for spastic paraplegia with thin CC. Magnetic resonance imaging (MRI) examination revealed a thin CC with fronto-parietal cortical atrophy. 18 Fluordesoxyglucose positron emission tomography (FDG–PET) showed reduced cortical and thalamic metabolism. By transcranial magnetic stimulation, we delineated a severe impairment of transcallosal inhibition. Sequence analysis did not reveal disease causing mutations in the genes SLC12A6 (Andermann), Spastin (SPG 4), BSCL2 (SPG 17) and Spartin (SPG 20). We reviewed the literature for HSP with thin CC and found 113 HSP patients with thin CC previously described (35 with linkage to chromosome 15q13–15). Thin CC and peripheral neuropathy often appear together in spastic paraplegia and might be indicative for combined degeneration mechanism of central and peripheral axons. © 2005 Elsevier B.V. All rights reserved. Keywords: Hereditary spastic paraplegia; Transcallosal inhibition; Neuropathy; SPG 11; Corpus callosum; Amyotrophy

1. Introduction The hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurodegenerative disorders where progressive gait disturbance predominates due to severe lower limbs spasticity and less pronounced weakness. HSP is clinically divided into “pure” and “complicated” forms. “Pure” forms show symptoms limited to progressive spastic weakness of the legs, accompanied by urinary urgency and subtle dorsal column impairment. In complicated forms, care∗ Corresponding authors. Tel.: +49 941 941 3340/3341; fax: +49 941 941 3005. E-mail addresses: [email protected] (B. Winner), [email protected] (J. Winkler).

0303-8467/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2005.06.007

ful differential diagnosis is necessary as additional neurological symptoms (e.g. mental retardation, epilepsy, ataxia, thin corpus callosum or neuropathy) or additional non-neuronal features (e.g. cataract, ichtyosis) occur (for review, see Ref. [1]). Genetically, HSPs are divided into autosomal dominant, autosomal recessive (AR) and X-linked recessive forms. Currently, 28 HSP gene loci and 11 HSP genes are known (for review, see Refs. [2,3]). The function of the genes associated with HSPs suggest a “dying back” of the terminal ends of the cortico-spinal tract axons due to defective axonal trafficking as the common underlying pathophysiological mechanism for several forms of HSP [2,4]. Complicated HSPs present not only with degeneration of the spinal cord (cortico-spinal and spino-thalamic tract), but

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also with cortical degeneration. We focus here on one special form described with thin corpus callosum (CC) as well as cortical atrophy. Interestingly, the peripheral nervous system (PNS) might also be affected with a sensorimotor neuropathy, indicating a generalized dysfunction of central and peripheral axons. A thin CC is present in some patients with complicated HSP. Genetic analysis of HSP with mental impairment, a thin CC and AR inheritance has identified one locus in chromosomal region 15q13–15 (SPG 11) [5]. Here, we clinically and genetically characterize a patient with spastic paraplegia with a thin CC and amyotrophy in a Caucasian pedigree and discuss the neurogenetic differential diagnosis of thin CC as well as amyotrophy in HSP.

2. Patient and methods 2.1. Medical history The index patient is a 37-year-old female of Caucasian descent, that was affected by a complicated form of spastic paraplegia. During childhood, she achieved normal motor milestones. Moreover, she was obese and her legs were massively swollen and hairless, indicating lymphedema (body mass index: 33). Her past medical history was otherwise not significant. She developed a slowly progressive gait disorder starting at the age of 29 years. Her walking distance decreased from 1 km at age of 32 years to 300 m at age of 37 years. Furthermore, the strength of the thenar and hypothenar muscles and the coordination of the hands were impaired. In addition, cognitive performance was below average. Neurological examination revealed severe bilateral spasticity, particularly in the hamstrings, quadriceps and ankles. Moreover, weakness of the lower limbs was present in ilipsoas, tibialis anterior, and to a lesser extent, the hamstrings. There was hyperreflexia of the lower limbs and extensor plantar responses. She had a slow, spastic and slightly ataxic gait, which worsened over time. A prominent amyotrophy of the hypothenar and thenar muscles was bilaterally present (Fig. 1). She was treated with Baclofen (20 mg daily) for her spasticity.

Fig. 1. Images of the hands of the index patient. Note the amyotrophy of the thenar (arrow) and hypothenar muscle.

2.4. Functional Functionally, transcranial magnetic stimulation, nerve conduction studies, concentric needle electromyography, FDG–PET and cognitive testing completed the clinical assessment.

2.2. Laboratory Analysis of the cerebro spinal fluid (CSF) for the presence of oligoclonal bands and a comprehensive blood testing for electrolytes, hormones, fats and vitamins, infectious and metabolic diseases (adrenoleukodystrophy and metachromatic leukodystrophy) was performed. 2.3. Structural Cerebral and spinal MRIs were carried out.

Fig. 2. Pedigree of complicated spastic paraplegia with a thin corpus callosum (CC) (filled circle: index patient).

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2.5. Genetic Blood samples from the index patient and four nonaffected family members were obtained after informed consent (pedigree; Fig. 2). The SLC12A6 gene (15q14) was screened for mutations. Moreover, DNA was tested for mutations in the genes Spastin (SPG 4, 2p21–22), BSCL2 (SPG 17, 11q12–14) and Spartin (SPG 20, 13q12.3).

3. Results 3.1. Serological analysis Blood tests and CSF analysis were within normal limits. Inflammatory and metabolic diseases leading to spastic paraplegia were excluded. 3.2. Structural analysis The cerebral MRI scans (FLAIR, T1, T2) showed a pronounced thinning of the rostral part of the CC, which appeared as a thin band in the mid-saggital T1 -weighted images (Fig. 3A). Frontal cortical atrophy and widening of the lateral ventricle were observed (Fig. 3B). MRI images of the spinal cord were normal, with the exception of a minimal protrusion at the C2/C3 disc. 3.3. Functional deficits FDG–PET showed hypometabolism in the fronto-parietal and temporal cortices as well as in the thalamus (Fig. 3C and D). The neuropsychological assessment revealed cognitive impairment (Hamburg Wechsler Intelligence Test for Adults: 62) presenting with intact long-term memory, but severe

attentional deficits. These results are in accordance with a report in subjects with callosal lesions [6], describing impairment of frontal functions but preserved temporal functions. Therefore, the neuropsychological profile corresponds to the expected profile of subjects with callosal lesions. After right-sided transcranial magnetic stimulation, the patient showed a delayed latency (62 ms—limits of normal range < 43.9 ms [7]) and an increased duration of the transcallosal inhibition (35 ms—limits of normal range < 32.6 ms [7] (Fig. 4A). After left-sided magnetic stimulation, a lack of transcallosal inhibition was present (Fig. 4B). This indicates a delayed or absent inhibitory response of the cortex via the CC compared to a healthy control (Fig. 4C). The low amplitude of the contralateral responses to transcranial magnetic stimulation was indicative of a lesion of the cortico-spinal tract. Using standard magnetic evoked potentials for the lower extremities no response was observed demonstrating a severe lesion of the cortico-spinal tract. Concentric needle electromyography was characteristic for a severe axonal loss polyneuropathy (Fig. 5A). Fibrillation potentials and positive sharp waves were found on concentric needle electromyography in both the hypothenar as well as anterior tibial muscles. Motor unit action potentials were of increased duration, amplitude and firing rate indicating a loss of motor axons. Moreover sensory demyeliniation was observed (Fig. 5B). All other family members were healthy and their BMI was normal. Moreover, the daughter of the index patient had a normal MRI of the cerebrum. No evidence of parental consanguinity was found. 3.4. Genetic analysis The clinical phenotype of a “complicated” form of HSP with thin CC led us to perform mutation analysis in genes

Fig. 3. Magnetic resonance (MR) images showing (A) thin corpus callosum (CC, see arrow) and (B) frontal atrophy (see arrows) as well as widening of the lateral ventricles. Images obtained with 18-fluorodeoxyglucose positron emission tomography (FDG–PET) demonstrate (C) fronto-parietal cortical and (D) thalamic (see star) hypometabolism.

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Fig. 4. Transcallosal inhibition in index patient with spastic paraplegia with a thin CC. Recordings are obtained from the first dorsal interosseus muscle contralateral and ipsilateral to the site of supramaximal stimulation of the motor cortex. (A) Right-sided magnetic stimulation: lack of transcallosal inhibition indicates absence of inhibitory responses across the CC. (B) Left-sided magnetic stimulation: delayed latency and increased duration of transcallosal inhibition indicates functional deficits in inhibitory responses across the CC (arrow). (C) Right-sided magnetic stimulation in a healthy control with intact inhibitory responses of the CC.

related to this disease entity. No mutation in coding regions or splice junctions was found in the genes SLC12A6, Spastin, BSCL2 and Spartin.

4. Discussion The present clinical observation is consistent with the diagnostic criteria for HSP with mental impairment and a thin CC [8]. Cortical atrophy is present in the MRI, paralleled by cortical and thalamic hypometabolism in the FDG–PET. Besides, the morphological thinning of the CC, the electrophysiological data demonstrates a functional deficit in inhibitory responses across the CC, which reflects dysfunctional cortico-cortical projections. No other family members are affected so that this patient is classified as “sporadic” complicated paraplegia. The clinical phenotype has previously been observed in families with linkage to 15q13–15, however, this assessment is not of use here, due to the family size. Neurogenetic analysis was carried out, involving genes associated with the present clinical phenotype (spastic paraplegia, severe hand muscle amyotrophy and thin CC). No mutation was found for the “Andermann” locus SLC12A6, Spartin and two genes associated with autosomal dominant HSP (Spastin and BSCL2).

4.1. Thin CC: a potential hallmark for the differential diagnosis of complicated HSP Complicated HSP may be distinguished based on genotype–phenotype correlations. We reviewed the literature for cases with HSP and thin CC (see Table 1). Taken these studies together, 113 patients with HSP with thin CC have been reported, half of them in Asia (Table 1). In only one-third of the patients (n = 35 out of 18 families), linkage to SPG 11 has been shown. It is important to note, that for a few patients (n = 9) with the present phenotype, linkage to SPG 11 was excluded indicating genetic heterogeneity [9,17]. Based on this review, the sole pedigrees with a known genetic defect other than SPG 11 were: (1) an Amish pedigree with 14 affected members (three of them described with thin CC) with mutations in the SPG 21 gene maspardin [10] and (2) moreover, two patients with mutation in the SPG 4 gene Spastin have been described with a thin CC [11]. Interestingly, most HSP patients with a thin CC had impaired cognitive performance. Most reports describe a thin CC, whereby MRI scans reveal a thinning more prominent in the anterior part of the CC truncus. Anatomical studies focusing on the spatial relationship between the cerebral hemispheres and fibre trajectory through the CC [12] have

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Table 1 Exhaustive review of cases reported in literature with HSP and thin CC SPG

Reference

No. of patients/ no. of families

Origin

Thin CC

White matter lesion

Mental retardation

11

[5] [9]

US Italian Japanese

+ + +

− +

11

+ + +

11

[16]

2/1 2/1 20/10, Hereby, 13 newly reported subjects 2/1

German

+

+

+

11

[17]

9/5

Italian

+

+

+

Did not map to 11 Did not map to 11

[17]

2/1

Italian

+

+

[9]

7/3, Hereby, 4 newly reported subjects 2/2 14/1

Japanese

+

+

Scottish Amish

+ + (MRI available for 3 patients from 14) + (In 17 patients)

− +

+

4 21

[11] [10]

Axonal loss and demyelinating sensorimotor neuropathy 1 patient; hand muscle amyotrophy Dysarthric speech

− +

Cerebellar atrophy Severe dementia

+

Extrapyramidal symptoms in 6 patients

[8] Including review of literature [17] [18] [19]

19/10 2/1

Japanese Spanish

7/6 1/1 3/1

Italian Japanese Japanese

+ + + (MRI from 1 patient)

[15]

2/1

Portuguese

+

[20] [21]

2/2 1/1

Brazilian Japanese

+ +

[22]

2/1

Japanese

[23]

2/1

Balkans

+ (Thinning of the posterior truncus) +

[24]

2/1

Austrian

+

+

+

[25] [26]

5/5 2/1

Chinese Taiwanese

+ +

−

+ ±

[27] [28]

2/1 1/1

German Japanese

+ +

− −

+ +

+ + +

+

+

Additional symptoms

+ +

+ +

Ataxia, cataracts and axonal neuropathy Patients with leukodystrophy excluded from study Cerebellar ataxia Neuropathological study, severe thalamic hypometabolism Cataract, mild cerebellar atrophy Dystonia and chorea Severe hand muscle atrophy Levodoparesponsive parkinsonism Amyotrophy Frontal atrophy

Papers were included if they were full paper citations; English peer-reviewed literature, excluding abstracts and books.

revealed that the anterior portion of the CC contains projections of the prefrontal and premotor cortex. 4.2. Neuropathy and amyotrophy in HSP Although slight neuropathy has been described in many forms of HSP, amyotrophy has mainly been observed in complicated HSP, mostly linked to HSP 17 and HSP 20 [13].

About, 10% of the patients with autosomal recessive HSP show an upper limb amyotrophy, about 26% present with lower limb amyotrophy [14,15]. In the present case, degeneration of cortico-cortical, as well as cortico-spinal and peripheral axons is present. We, therefore, hypothesize, that thin CC and neuropathy might be indicative of axonal degeneration of central and peripheral axons.

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Fig. 5. (A) Concentric needle electromyogram obtained from the hypothenar muscles. The upper trace shows positive sharp waves and the lower trace shows motor unit action potentials with increased amplitude of 2.9 mV and maximal discharge rate of 22 s−1 that indicate chronic axonal damage. (B) Near-nerve recording from the left sural nerve. The arrows point to abnormal late components that indicate demyelination of sensory nerve fibers.

Acknowledgments We thank the patient and her family for their participation and the Tom Wahlig foundation (Jena, Germany) for support. B.W. and G.U. were fellows of the “Regensburger Forschungsf¨orderung in der Medizin” of the School of Medicine, University of Regensburg, Germany. Moreover, we thank Bernhard Grigo and Petra Schopf for their excellent technical assistance. The authors thank G. Schuierer (Institute for Neuroradiology, Bezirksklinikum Regensburg) and L.J. Thal (Department of Neurosciences, La Jolla, USA) for continuous support and critical reviews.

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