A rare case of adult-onset spastic paraparesis associated with Klinefelter syndrome.

REPORT: The rare association of Klinefelter syndrome and the clinical presentation of a late onset chronic progressive spastic paresis. CLINICAL PRESENTATION AND GENETICS: An infertile, 61-year-old man, presented with late adult onset of gait problems, deep muscle pain, and bladder problems. He presented for the first time, years after onset with a spastic paraparesis with high arched feet. His parents had already died, but the patient described high arched feet with his mother. There is no further certain information about the parents. After thorough investigation, an additional X chromosome was found, whereafter the diagnosis of Klinefelter syndrome could be made. Other acquired and genetic causes for spastic paraparesis or hereditary motor neuropathy are excluded. CONCLUSION: This rare case, together with three other literature reports by Sasaki (Intern Med 58(3):437-440, 2019), Sajra (Med Arh 61(1):52-53, 2007) and Matsubara et al., (J Neurol Neurosurg Psychiatry 57(5):640-642, 1994). suggests that Klinefelter syndrome can be associated with spastic paraparesis, besides the other various neuropsychiatric symptoms that are more commonly described.

Potential beneficial effects of granulocyte colony-stimulating factor therapy for spastic paraparesis in a patient with kyphoscoliosis: a case report.

Congenital kyphosis and kyphoscoliosis are much less common than congenital scoliosis and more serious because these curves can progress rapidly and can lead to spinal cord compression and paraplegia. A 15-year-old boy presented with congenital kyphoscoliosis along with spastic paraparesis (American Spinal Injury Association Impairment Scale grade C). We examined the safety and effectiveness of a low dose of analog granulocyte colony-stimulating factor (G-CSF) in this patient. G-CSF 5 µg/kg was given subcutaneously, daily for 5 days per month for 3 months. Laboratory tests, including blood, biochemical tests, and CD34+ cells (marker hematopoietic progenitor cells) were performed, in addition to clinical examination. Clinical examination revealed an increase of muscle strength in the upper limbs and decrease spasticity in the lower limbs between baseline and day 90 and day 180. We found no serious adverse event, drug-related platelet reduction, or splenomegaly. Leukocyte levels remained below 21,000/µL. CD34+ increased significantly at day 5 of G-CSF administration. Low-dose G-CSF was safe and well tolerated by the patient. A significant increase in muscle strength in this patient with spastic paraparesis after 3 months of treatment may indicate beneficial effects of G-CSF factor in this disorder. These results are inspiring and warrant further studies.

Spastic paraparesis and marked improvement of leukoencephalopathy in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder with inflammatory immune-mediated pathogenesis. Disease onset is most commonly marked by recurrent fevers, irritability, and developmental regression in the 1st year of life. A stable phase characterized by severe spastic quadriparesis and cognitive deficit follows. Brain calcifications, leukoencephalopathy, and cerebral atrophy are the radiological hallmarks of AGS and often show progression over time. We present an atypical patient with late-onset AGS characterized by spastic paraparesis and a leukoencephalopathy that markedly improved during follow-up, demonstrating a nonprogressive disease course and the exceptional amelioration of the white matter abnormalities.

The effects of functional electrical stimulation on walking in hereditary and spontaneous spastic paraparesis.

OBJECTIVES: To investigate in people with spastic paraparesis (SP): 1) the factors contributing to foot drop and reduced toe clearance while walking; 2) short-term effects of bilateral functional electrical stimulation (FES) of the common peroneal nerve. MATERIALS AND METHODS: Long term (>0.5 years) users of FES with SP were compared to matched controls (N = 11 per group). Ankle strength and plantarflexor stiffness and walking kinematics were objectively recorded. The effects of FES on: 1) perceived efficacy; 2) muscle torque and ankle motion; 3) clinical outcome measures and walking kinematics were assessed. Results were compared using an analysis of covariance. RESULTS: Ankle weakness and stiffness is higher among people with SP. Higher plantarflexor stiffness is associated with reduced swing phase dorsiflexion; higher toe clearance while walking is associated with increased hip flexion. FES increases dorsiflexor torque, improves toe clearance and dorsiflexion in swing phase, and significantly improves walking speed (p < 0.05). CONCLUSIONS: There are multiple causes of tripping in people with SP; FES reduces foot drop and improves walking speed.

[Early-onset familial Alzheimer's disease with spastic paraparesis associated with PSEN1 gene]. / Rannyaya semeinaya bolezn' Al'tsgeimera so spasticheskim paraparezom, svyazannaya s genom PSEN1.

A familial case of a rare autosomal dominant Alzheimer's disease (AD), related to PSEN1 gene (AD3, OMIM 607822), differing from common multifactorial form by earlier onset and, in part of cases, by accompanying neurological signs, spastic paraparesis particularly, is presented. The first sign in a female proband and in her son was paraparesis manifested at the age of 29 and 21 years, respectively. Cognitive disturbances developed soon; the former diagnosis was hereditary spastic paraplegia with cognitive impairment, In the proband examined in 2008 at 33 years old the diagnosis was not established. In the son examined in 2022 at 27 years old whole-exome sequencing detected a novel PSEN1 missense mutation p.Thr421Ala. The mutation was confirmed by Sanger sequencing in him, found out in the proband (who was severely disabled by that time) and excluded in her unaffected mother. Except for different age of onset, AD3 in two patients was similar, though in whole it is variable, also in relatives. The variability and rareness of the disease hampers clinical diagnostics. Massive parallel sequencing is a most reliable diagnostic method.

Clinical and Molecular Findings in a Turkish Family Who Had a (c.869- 1G>A) Splicing Variant in PSEN1 Gene with A Rare Condition: The Variant Alzheimer's Disease with Spastic Paraparesis.

BACKGROUND: Early-onset Alzheimer's disease (EOAD) is commonly diagnosed with an onset age of earlier than 65 years and accounts for 5-10% of all Alzheimer's disease (AD) cases. To date, although only 10-15% of familial EOAD cases have been explained, the genetic cause of the vast proportion of cases has not been explained. The variant Alzheimer's disease with spastic paraparesis (var- AD) is defined as a rare clinical entity characterized by early-onset dementia, spasticity of the lower extremities, and gait disturbance. Although the disease was first associated with variants in exon 9 of the PSEN1 gene, it was later shown that variations in other exons were also responsible for the disease. OBJECTIVE: The current study aims to raise awareness of varAD, which occurs as a rare phenotype due to pathogenic variants in PSEN1. In addition, we aimed to evaluate the spectrum of mutations in varAD patients identified to date. METHODS: Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family was done by Sanger sequencing. Also, a review of the molecularly confirmed patients with (varAD) from the literature was evaluated. RESULTS: We identified a heterozygous splicing variant (c.869-1G>A) in the PSEN1 gene, in a family with two affected individuals who present with varAD. We reported the clinical and genetic findings from the affected individuals. CONCLUSION: We present the detailed clinical and genetic profiles of a Turkish patient with the diagnosis of varAD together with subjects from the literature. Together, we think that the clinical characteristics and the effect of the (c.869-1G>A) variant will facilitate our understanding of the PSEN1 gene in AD pathogenesis.

Progressive cognitive impairment and familial spastic paraparesis due to PRESENILIN 1 mutation: anatomoclinical characterization.

INTRODUCTION: Autosomal dominant Alzheimer's disease (ADAD) due to presenilin 1 (PSEN1) mutation can induce atypical neurological symptoms such as movement disorders and epileptic seizures in the context of early-onset progressive cognitive impairment. METHODS: This study includes the anatomoclinical description of three patients of two generations of the same family with movement disorders and progressive cognitive impairment. All were evaluated by trained neurologists, underwent protocolized neuropsychological evaluation, and were assessed by structural (magnetic resonance) and functional (SPECT, PET-18FDG, or PET-18F-Florbetapir) brain imaging tests. A molecular genetic study was performed for all patients, and post-mortem confirmatory anatomopathological evaluation for one of them. RESULTS: The three female patients had an age of onset of symptoms of 38-51 years. All developed progressive multidomain cognitive impairment, paraparesis, and dysarthria, two with ophthalmoparesis and one with untriggered epileptic seizures since early stages. Bilateral cortical fronto-parietal atrophy and global cortical hypoperfusion or posterior bilateral hypometabolism were detected. PET-18F-Florbetapir, when performed, was positive for amyloid cortical deposit. The molecular genetic study confirmed the PSEN1 mutation c.869-2 A>G. Postmortem study of one of them confirmed Alzheimer's disease anatomopathological features with classic cotton wool plaques (CWP), including coexistence of amyloid angiopathy and Lewy body co-pathology. DISCUSSION: The phenotype of ADAD due to PSEN1 mutations is very heterogeneous between and across the same family. Family history assessment should include information not only about cognitive decline, but also about movement disorders and untriggered epileptic seizures. Further studies are needed to identify genetic or epigenetic factors that determine phenotypic diversity in this disease.

Revisiting Konzo Risk Factors in Three Areas Differently Affected by Spastic Paraparesis in Eastern Democratic Republic of the Congo Discloses a Prominent Role of the Nutritional Status-A Comparative Cross-Sectional Study.

This comparative cross-sectional study aimed to better understand the respective contributions of protein malnutrition and cassava-derived cyanide poisoning in the development of konzo. We compared data on nutritional status and cyanide exposure of school-age adolescent konzo-diseased patients to those of non-konzo subjects of similar age from three areas in the Eastern Democratic Republic of the Congo. Our results show that konzo patients had a high prevalence of both wasting (54.5%) and stunting (72.7%), as well as of cyanide poisoning (81.8%). Controls from Burhinyi and those from Idjwi showed a similar profile with a low prevalence of wasting (3.3% and 6.5%, respectively) and intermediate prevalence of stunting (26.7% and 23.9%, respectively). They both had a high prevalence of cyanide poisoning (50.0% and 63.0%, respectively), similar to konzo-patients. On the other hand, controls from Bukavu showed the lowest prevalence of both risk factors, namely chronic malnutrition (12.1%) and cyanide poisoning (27.6%). In conclusion, cassava-derived cyanide poisoning does not necessarily coexist with konzo outbreaks. The only factor differentiating konzo patients from healthy individuals exposed to cyanide poisoning appeared to be their worse nutritional status. This further suggests that, besides the known role of cyanide poisoning in the pathogenesis of konzo, malnutrition may be a key factor for the disease occurrence.

Cognitive profile in spastic paraplegia with thin corpus callosum and mutations in SPG11.

Autosomal recessive hereditary spastic paraplegia with thinning of the anterior corpus callosum (ARHSP-TCC) due to mutations in SPG11 on chromosome 15q (MIM610844) is the single most common cause of ARHSP. It is characterized by slowly progressive paraparesis and peripheral neuropathy. Although cognitive impairment, sometimes diagnosed as mental retardation, is an almost invariable feature, the extent and specific neuropsychological features are not fully understood. We report a comprehensive neuropsychological assessment in two ARHSP-TCC patients harbouring mutations in SPG11. A specific impairment in executive functions occurring even before cognitive decline, may be considered the core of the neuropsychological profile of patients harbouring mutations in SPG11.

Amygdala size reduction is associated with memory deficits in complicated hereditary spastic paraparesis: an MRI study.

Neuroimaging findings in hereditary spastic paraparesis (HSP), especially in complicated HSP (cHSP), are heterogenous. This study aimed to investigate possible in vivo morphological alterations of the whole brain and the amygdala in cHSP as a correlate of cognitive impairment in contrast to pure variants (pHSP). Amygdalar and whole brain volumes of 33 HSP patients (21 pHSP and 12 cHSP) were measured using three-dimensional magnetic resonance imaging (MRI) data sets by region of interest-based volumetry. A neuropsychological test battery was also performed. A significant reduction in whole brain volume compared with the controls, as well as significant correlations with reduced amygdalar volume and a worse neuropsychological test performance was observed only in cHSP patients. Our findings of disproportional amygdalar atrophy only in cHSP substantiate the association of morphologically assessable cerebral degeneration with cognitive impairment in cHSP.

[A case of spastic paraplegia 48 with a novel mutation in the AP5Z1 gene].

We describe an additional patient with spastic paraplegia 48 (SPG48). A 52-year-old woman with gradually increasing gait disturbance was admitted to our hospital. When she was 47 years old, acquaintances noted a shuffling gait. Gait worsening was evident at 48 years. Spastic gait was apparent at 50, and she required a walking stick at 54. Her elder brother had similar gait disturbance. No consanguinity was known. Neurologic examination at 52 disclosed spasticity and moderate weakness in the lower limbs. Spasticity and brisk reflexes in all limbs. Laboratory studies including HTLV-1 titer detected no abnormalities. MRI demonstrated mild corpus callosum narrowing and prominent anterior periventricular hyperintensities in fluid attenuation inversion recovery images. In limb muscles, electromyography (EMG) showed a chronic neurogenic pattern including reduced interference. Gene analysis identified compound homozygosity in exon 7 of adaptor-related protein complex 5 subunit zeta 1 (AP5Z1), including a novel frameshift mutation, c.1662_1672del;p.Glu554Hfs*15 in the patient, and a heterozygous missense mutation in asymptomatic family members, including her mother, two siblings, and a daughter. The frameshift mutation is considered a pathogenic variant according to American College of Medical Genetics and Genomics standards and guidelines. Based on clinical features, imaging findings and genetic abnormalities, we diagnosed this patient with SPG48. Mutations in AP5Z1, which encodes the ζ subunit of AP-5, underlie SPG48. The AP-5 adaptor protein complex, which is mutated in SPG48, binds to both spastizin and spatacsin. While hereditary spastic paraplegias generally are clinically and genetically heterogenous, SPG48, SPG11, and SPG15 are clinically similar.

Variable phenotype of Alzheimer's disease with spastic paraparesis.

Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid beta peptide (Abeta) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid beta peptide starting after the alternative beta-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.

Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: a diagnostic approach.

Spastic paraparesis is a general term describing progressive stiffness and weakness in the lower limbs caused by pyramidal tract lesions. This clinical situation is frequently encountered in adult neurology. The diagnostic survey is usually limited to searching for acquired causes (spinal cord compression, inflammatory, metabolic, infectious diseases) and the so-called 'hereditary spastic paraparesis'. Although poorly recognized by neurologists, spastic paraparesis is also one of the multiple presentations of inborn errors of metabolism (IEMs) in children and adults. Pyramidal signs are usually included in a diffuse neurological or systemic clinical picture; however, in some cases spastic paraparesis remains the only symptom for years. Since these metabolic causes are often treatable, it is essential to include them in the general diagnostic approach to spastic paraparesis. Here we review IEMs causing paraparesis in adults.

A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis.

Early onset familial Alzheimer's disease (EOFAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. Several families with an association of progressive dementia and spastic paraplegia caused by PSEN1 mutations have been described. Here we described a novel PSEN1 mutation that was associated with dementia and spastic paraplegia in a family with 5 affected individuals in three generations. The proband was a 44-year-old woman who presented with 5 years history of progressive difficulties in walking, cognition and visuospatial impairment. Her maternal grandmother, mother and two maternal aunts also had similar neurological presentation. Molecular genetic analysis showed a missense mutation predicted to substitute an arginine residue for a serine residue at position 278 in the PSEN1 polypeptide (Arg278Ser). The novel PSEN1 mutation identified in this patient adds to the diverse list of existing mutations causing EOFAD associated with spastic paraparesis.

Paraneoplastic acute disseminated encephalomyelitis associated with multiple myeloma.

We describe a man recently diagnosed with multiple myeloma who presented with progressive spastic paraparesis, encephalopathy and multifocal MRI lesions with haemorrhage. Brain histopathology was consistent with acute disseminated encephalomyelitis (ADEM) with no new clinicoradiological findings on follow-up. This case emphasises the growing paraneoplastic spectrum, including non-classical but treatable disorders such as ADEM.