A Case Report of Amyotrophic Lateral Sclerosis in a Patient With Klippel–Feil Syndrome—a Familial Occurrence

Abstract

The rationale for this article is a description of a unique, familial case of a patient with amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder of unknown etiology coexisting with Klippel–Feil syndrome (KFS), a congenital malformation of cervical vertebrae, characterized by a fusion of minimum 2 cervical vertebrae.We report a 68-year-old man with moderate dysarthria, fasciculations, short neck, hearing deficit, and low posterior hairline. Definite ALS was diagnosed based on neurological abnormalities and electromyography results. Magnetic resonance imaging and computed tomography showed bony abnormalities of the craniocervical junction, fusion of 2 cervical vertebrae, and syringomyelia at the level of C6-C7. KFS phenotype was noted in 2 more family members, and patient's stepsister with KFS phenotype died due to ALS.The pedigree of our family suggests an autosomal-dominant inheritance of both syndromes. Cosegregation of ALS and KFS with an autosomal-dominant trait suggests an impairment of transforming growth factor β signaling pathway, and its potential role is discussed. Further evaluation of patients with autosomal-dominant and sporadic KFS by genetic testing, biochemical measurements, such as plasma transforming growth factor β1, and systematic follow-up electromyography seems warranted.

Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types

“…Pathway analysis revealed a remarkable loss of TGFβ pathway activity in oligodendrocytes from ALS patients, suggesting a pathogenic role for loss of TGFβ pathway activity in this disease. This finding is in full agreement with reports describing loss-of-function mutations in the ZNF512B gene that result in loss of TGFβ pathway activity and are associated with susceptibility to, and more aggressive, ALS 68,69 . Recently, an elegant mouse model revealed that loss of TGFβ pathway activity in glia cells causes demyelinating diseases 70 .…”

Clinical cases of amyotrophic lateral sclerosis concurrent with hydromyelia

“…Clinical signs of the upper and lower motor neuron deficits in the cervical, thoracic, and lumbar regions supported by the results of electrophysiological and biochemical testing led to a diagnosis of ALS. 15 Therefore, it can be concluded that this is a very rare combination. Taking into account the fact that hydromyelia is a phenotypic feature of some neurodegenerative diseases, 8,9 there is a possibility that hydromyelia may be a part of the phenotype in the rare cases of ALS.…”

“…After a diagnostic work‐up the cervical syringomyelia was excluded as the cause of the symptoms observed in the patient. Clinical signs of the upper and lower motor neuron deficits in the cervical, thoracic, and lumbar regions supported by the results of electrophysiological and biochemical testing led to a diagnosis of ALS 15 …”

Syringomyelia: A New Phenotype of SPG11-Related Hereditary Spastic Paraplegia?

“…Authors of one study including nine MS patients with syringomyelia concluded that syringomyelia was not a coincidental finding but likely associated with MS pathophysiology, considering the low prevalence of syringomyelia in the normal population [ 24 ]. Syringomyelia was also recently reported in patients with amyotrophic lateral sclerosis (ALS) [ 25 26 ], while a study using MRI data to study CSF dynamics revealed different CSF hydrodynamics in ALS patients compared to healthy controls [ 27 ]. The mechanism behind syrinx formation in these patients is uncertain at this point, but drawing these findings together, one could hypothesize that the neurodegenerative change in nerve tissue might alter normal CSF drainage from the central canal.…”