Familial spastic paraplegia with mental impairment and thin corpus callosum

doi:10.1016/0022-510X(95)00028-Z

Journal of the Neurological Sciences

Volume 131, Issue 1, July 1995, Pages 35-42

https://doi.org/10.1016/0022-510X(95)00028-Z Get rights and content

Abstract

We described four patients in two families of unique familial spastic paraplegia (FSP) which was thought to be possibly autosomal recessive inheritance. All four patients had quite similar manifestations. Gait disturbance started at their second decade, then spastic paraparesis and mental deterioration progressed slowly. Cerebellar ataxia and sensory loss in the distal parts of four extremities were also slightly presented. In all patients, cranial MRI revealed marked thin corpus callosum with mild changes in the region of periventricular white matter and in the gray matter. Biopsied sural nerves of all patients showed chronic axonal degeneration with mild decrease of both large and small myelinated fibers. Electron microscopic study demonstrated crystalline-like inclusion bodies in the cytoplasm of Schwann cells in all patients. Despite extensive investigation for metabolic disorder, we could not find any abnormality. However an etiology have not established at the time presented, the combination of these clinical features suggested that the disorder could represent a specific clinical entity.

References (30)

F.S. Bamforth et al.
Abnormalities of corpus callosum in patients with inherited metabolic diseases
Lancet
(1988)
B. Robinson et al.
Variable clinical expression in patients with defective E1 component of pyruvate dehydrogenase complex
J. Pediatr.
(1987)
J. Aicardi et al.
A new syndrome: spasms in flexion, callosal agenesis, ocular abnormalities
Electroenceph. Clin. Neurophysiol.
(1965)
J. Aicardi et al.
Agenesis of the corpus callosum
F. Andermann et al.
Familial agenesis of the corpus callosum with anterior horn-cell disease: a syndrome of mental retardation, areflexia and paraparesis
Trans. Am. Neurol. Assoc.
(1972)
A.J. Barkovich et al.
Anomalies of the corpus callosum: correlation with further anomalies of the brain
AJR
(1988)
A. Cao et al.
Agenesis of the corpus callosum, infantile spasms, spastic quadriplegia, microcephaly and severe mental retardation in three siblings
Clin. Genet.
(1977)
C.C. Carleton et al.
Subacute necrotizing encephalopathy (Leigh's disease): two unusual cases
South Med. J.
(1976)
K.H. Chang et al.
Marchiafava-Bignami disease: serial changes in corpus callosum on MRI
Neuroradiology
(1992)
H.D. Davidson et al.
Agenesis of the corpus callosum: magnetic resonance imaging
Radiology
(1985)

J.L. Dietemann et al.

Multiple sclerosis and corpus callosum atrophy: relationship of MRI findings to clinical data

Neuroradiology

(1988)

W.B. Dobyns

Agenesis of the corpus callosum and gyral malformations are frequent manifestations of nonketotic hyperglycinemia

Neurology

(1989)

S. Gilman et al.

Familial amyotrophic dystonic paraplegia

Brain

(1964)

K. Hayasaka et al.

Nonketotic hyperglycinemia: two patients with primary defects of P-protein and T-protein, respectively, in the glycine cleavage system

Pediatr. Res.

(1987)

Y. Honda et al.

Familial cases of spastic paraparesis, mental disturbance and thinning of the corpus callosum

Rinsho Shinkeigaku (Japan)

(1993)

Cited by (72)

Interacting with AP1 complex mutated synergin gamma (SYNRG) reveals a novel coatopathy in the form of complicated hereditary spastic paraplegia
2022, Brain and Development
Citation Excerpt :
In addition, mild cerebral atrophy, dilatation in the bilateral lateral ventricle and third ventricle, and thinning of the trunk and splenium of the corpus callosum were observed in the cranial MRI of the patient. The clinical and imaging findings observed in our patients have also been reported in phenotypes caused by gene mutations encoding AP-4 and AP-5 coat proteins [12–15]. With these findings, we thought that the preliminary diagnosis of the patients might be compatible with a complicated hereditary spastic paraplegia phenotype with a wide clinical spectrum.
Today, it is known that about 80 genes are involved in the etiology of hereditary spastic paraplegia. However, there are many cases whose etiology could not be determined by extensive genetic tests such as whole-exome sequencing, clinical exome.
Candidate genes were determined, since no clinically illuminating variant was detected in the whole-exome sequencing analysis of three patients, two of whom were siblings, with a complex hereditary spastic paraplegia phenotype.
The p.Leu1202Pro variant in the SYNRG gene in the 1st and 2nd cases, and the p.Gly533* variant in the 3rd case were homozygous.
We suggest that the SYNRG gene interacting with AP-1 (adaptor-related protein) from the AP complex family may cause the complex hereditary spastic paraplegia phenotype with extensive clinical spectrum. It may be important to evaluate SYNRG gene variants in patients with hereditary spastic paraplegia whose etiology has not been clarified.
Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases
2020, Brain Research
Citation Excerpt :
A majority of the identified mutations implicated in ALS5 are predicted to result in truncated proteins (Orlacchio et al., 2010). SPG11 is a recessive disorder with significant phenotypic variability characterized by spastic movement of the lower limbs, progressive weakness, and a thin corpus callosum (Nakamura et al., 1995). Many patients also experience the development of a sensorimotor peripheral neuropathy and cognitive impairment.
Charcot-Marie-Tooth (CMT) disease is a progressive and heterogeneous inherited peripheral neuropathy. A myriad of genetic factors have been identified that contribute to the degeneration of motor and sensory axons in a length-dependent manner. Emerging biological themes underlying disease include defects in axonal trafficking, dysfunction in RNA metabolism and protein homeostasis, as well deficits in the cellular stress response. Moreover, genetic contributions to CMT can have overlap with other neuropathies, motor neuron diseases (MNDs) and neurodegenerative disorders. Recent progress in understanding the molecular biology of CMT and overlapping syndromes aids in the search for necessary therapeutic targets.
Novel SPG11 mutations in Chinese families with hereditary spastic paraplegia with thin corpus callosum
2013, Parkinsonism and Related Disorders
Citation Excerpt :
HSP is clinically divided into pure forms, where the spastic paraplegia is the major clinical manifestation, and complicated forms which are presented with additional neurological features including ataxia, mental retardation, peripheral neuropathy, visual impairment, seizures, etc [1,2]. HSP with thin corpus callosum (TCC) (MIM 604360) is a disorder characterized by slowly progressive paraparesis, cognitive impairment and axonal neuropathy [3]. Remarkable thinning of the corpus callosum and white matter abnormalities are the distinctive features visualized by brain magnetic resonance imaging (MRI).
Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Mutations in SPG11 gene have been recently identified as a major cause of hereditary spastic paraplegia with thin corpus callosum.
Two unrelated Chinese families were examined by clinical evaluation, mutation analysis of SPG11, detailed neuropsychological assessment and diffusion tensor imaging.
Both patients presented with spastic paraparesis and learning disability. Two novel and one known mutations in SPG11 were detected through genetic analysis. Cognitive impairment was found with severe deficits in domains such as executive functions and memory. Magnetic resonance imaging showed thin corpus callosum while diffusion tensor imaging revealed increased mean diffusion and decreased fractional anisotropy in the corpus callosum and subcortical white matter in frontal, temporal lobe compared with the healthy controls.
This study widens the spectrum of mutations in SPG11. The application of detailed neuropsychological tests and diffusion tensor imaging could detect cerebral subtle involvement even in early stage of the disease.
Hereditary Spastic Paraplegia
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Novel mutations of the SPG11 gene in hereditary spastic paraplegia with thin corpus callosum
2008, Journal of the Neurological Sciences
Citation Excerpt :
Additional symptoms include occasional seizures, peripheral neuropathy, cerebellar ataxia, extrapyramidal signs, and skeletal deformity. Brain magnetic resonance imaging (MRI) shows remarkable thinning of the corpus callosum [8–10]. Since originally described in four Japanese patients from the two different families by Nakamura et al., [8] HSP–TCC has also been reported in many other countries [11–18], and confirmed to have a worldwide distribution.
Hereditary spastic paraplegia with thin corpus callosum (HSP–TCC) is a clinically and genetically heterogeneous neurodegenerative disorder with genetic linkage to multi-loci. Recently pathogenic mutations in the KIAA1840 (now named SPG11) for SPG11, the major HSP–TCC locus, were identified; at least 42 different mutations have been detected.
To study the clinical features and identify the SPG11 gene mutations in Chinese patients with HSP–TCC.
Three kindreds with an autosomal recessive HSP–TCC and 5 cases with sporadic HSP–TCC in Chinese Hans were recruited. Detailed clinical history, neurological examination, MRI, electromyography, Mini Mental State Examination (MMSE), Spastic Paraplegia Rating Scale (SPRS) were presented. DNA samples of the 8 families were collected and mutation analysis of SPG11 gene was carried out by direct DNA sequencing.
Except for one patient whose age at onset was 3 years old, 10 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain MRI. We identified 10 novel and one known mutations in our 8 HSP–TCC families, which were two nonsense mutations (c.5977C>T/p.Q1993X, c.4668T>A/p.Y1556X), three small deletions (c.6898_6899delCT/p.L2300AfsX2338, c.3719_3720delTA/p.I1240VfsX263, c.733_734delAT/p.M245VfsX246), four small insertions (c.7088_7089insATTA/p.Y2363X, c.2163_2164insT/p.I722YfsX731, c.7101_7102insT/p.K2368X, c.6790_6791insC/p.L2264PfsX2339), one deletion/insertion (c.654_655delinsG/p.S218RfsX219), and one splice mutation (c.7151+4_7151+7delAGTA/p.K2384fsX2386). Each family has a different mutation and all the mutations are predicted to cause early protein truncation.
This study widens the mutation spectrum of the SPG11 gene and the mutations in the SPG11 gene are also the major causative gene for HSP–TCC in the Chinese Hans. Screening of the whole gene is recommended in clinical practice.
Diffusion tensor imaging of two unrelated Chinese men with hereditary spastic paraplegia associated with thin corpus callosum
2008, Neuroscience Letters
Hereditary spastic paraplegia (HSP) associated with thin corpus callosum is a rare autosomal recessive neurodegenerative disorder characterized by an abnormally thin corpus callosum, normal motor development, slowly progressive spastic paraparesis and cognitive deterioration. To investigate and localize abnormalities in the brains of two Chinese patients with HSP-TCC, with mutations in the spatacsin gene. Diffusion tensor imaging (DTI) was used to determine the mean diffusion (MD) and fractional anisotropy (FA) in the brains of the patients in comparison to 20 healthy subjects. Voxel-based analysis (VBA) of both the diffusion and anisotropy values were performed using statistical parametric mapping (SPM). Significant changes with MD increase and FA reduction were found in the already known lesions including the corpus callosum, cerebellum and thalamus. In addition, changes were also found in regions that appear to be normal in conventional MRI, such as the brain stem, internal capsule, cingulum and subcortical white matter including superior longitudinal fascicle and inferior longitudinal fascicle. Neither increase in FA nor reduction in MD was detected in the brain. Our study provides clear in vivo MR imaging evidence of a more widespread brain involvement of HSP-TCC. MD is more sensitive than FA in detecting lesions in thalamus and subcortical white matter, suggesting that MD may be a better marker of the disease progression.

View all citing articles on Scopus

View full text

Research articleFamilial spastic paraplegia with mental impairment and thin corpus callosum

Abstract

Lancet

J. Pediatr.

A new syndrome: spasms in flexion, callosal agenesis, ocular abnormalities

Electroenceph. Clin. Neurophysiol.

Agenesis of the corpus callosum

Familial agenesis of the corpus callosum with anterior horn-cell disease: a syndrome of mental retardation, areflexia and paraparesis

Trans. Am. Neurol. Assoc.

Anomalies of the corpus callosum: correlation with further anomalies of the brain

AJR

Agenesis of the corpus callosum, infantile spasms, spastic quadriplegia, microcephaly and severe mental retardation in three siblings

Clin. Genet.

Subacute necrotizing encephalopathy (Leigh's disease): two unusual cases

South Med. J.

Marchiafava-Bignami disease: serial changes in corpus callosum on MRI

Neuroradiology

Agenesis of the corpus callosum: magnetic resonance imaging

Radiology

Multiple sclerosis and corpus callosum atrophy: relationship of MRI findings to clinical data

Neuroradiology

Agenesis of the corpus callosum and gyral malformations are frequent manifestations of nonketotic hyperglycinemia

Neurology

Familial amyotrophic dystonic paraplegia

Brain

Nonketotic hyperglycinemia: two patients with primary defects of P-protein and T-protein, respectively, in the glycine cleavage system

Pediatr. Res.

Familial cases of spastic paraparesis, mental disturbance and thinning of the corpus callosum

Rinsho Shinkeigaku (Japan)

Research article
Familial spastic paraplegia with mental impairment and thin corpus callosum