Pure Hereditary Spastic Paraplegia in a Patient With a Novel Heterozygous KIDINS220 Gene Mutation

This case presents a somewhat unique and different phenotype of hereditary spastic paraplegia from previously reported kinase D-interacting substrate of 220 kDa (KIDINS220) gene mutation-related disease. We report a unique putative causative heterozygous mutation in KIDINS220 in a pure hereditary spastic paraplegia (HSP) patient expanding the HSP group further. We also deliberate on how our case was different from prior KIDINS220-related pathologies including spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome, and the observation of KIDINS220 and aquaporin-4 (AQP4) downregulation in the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. These findings warrant further investigations of the biology of KIDINS220. With the advent of new gene editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), variants such as ours provide an opportunity for targeted precision medicine.


Introduction
Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders characterized by spasticity and weakness in the lower limbs, stemming from degeneration of the corticospinal tract.HSP is categorized into two main types: (i) Pure HSP, which primarily involves spastic paraparesis with minimal sensory symptoms, and (ii) Complex HSP which includes additional neurological and non-neurological features [1].
The inheritance patterns can be autosomal dominant, autosomal recessive, or X-linked, with sporadic cases accounting for 13-40% of all reported cases [2].Kinase D-interacting substrate of 220 kDa (KIDINS220) encodes a conserved membrane protein that has 11 ankyrin repeats and four transmembrane domains [3].It is a scaffold protein involved in signal transduction, thereby playing crucial roles in neuronal cell survival, synaptic plasticity, and B and T cell activation and development [4].Apart from its role in neurotrophic pathways in neurons, it was also shown to be required for the establishment of proper neuronal connectivity and in astrocyte-neuron communication [5].

Case Presentation
A 23-year-old Caucasian female presented with long-standing progressive gait difficulty and lower extremity stiffness that began to occur seven years prior to this presentation.At that time, extensive workup was performed which was negative including magnetic resonance imaging (MRI) of the entire neuroaxis.No genetic testing was performed since there was no family history of gait abnormality reported.At this presentation, the patient also reported mild dysarthria, slight difficulty performing fine motor movements of the upper extremities likely attributable to very minimal coordination deficits, and urinary urgency, with otherwise no sphincter dysfunction.Her medical history was unremarkable; she had a normal birth and no developmental delay.Her family history was unremarkable as well.The patient did not have any psychiatric conditions.
The general examination was unremarkable and there were no deformities -she had no history of developmental anomalies or any cognitive delay.Her neurological examination demonstrated mild dysarthria, bilateral upper extremities' postural tremor, spasticity of the lower extremities (Modified Ashworth Scale 2), exaggerated knee (+3) and ankle (4+) deep tendon reflexes with sustained bilateral ankle clonus and bilateral up-going plantar reflexes.At the time of the visit, she was cognitively intact with good recall, intact attention, and comprehension.She had a normal cranial nerve exam and no concerns were raised for diplopia.Her visual acuity testing and visual field testing were also negative.Her ophthalmologic exam did not reveal any optic disc abnormalities and she had no visual complaints.The sensory exam was normal for all modalities.She had normal tone and reflexes in the upper extremities, and no cerebellar signs were noted.
Work-up for non-structural causes including routine blood tests, thyroid-stimulating hormone (TSH), vitamin B12, copper serum level, ceruloplasmin levels, vitamin E level, HIV, rapid plasma reagin (RPR), homocysteine and plasma very long chain fatty acids were negative.Liver function tests and lipid panel were also unremarkable.We also performed basic cerebrospinal fluid (CSF) testing which was unremarkable.CSF testing for the autoimmune panel and infectious etiologies were also negative.MRI of the brain and spine with and without contrast was repeated and was unremarkable again.Since the workup for compressive and non-compressive myelopathy was unremarkable and the examination findings of spasticity in lower extremities sparing the upper extremities were present, HSP was suspected, and a genetic panel was sent following genetic counseling.
Next-generation sequencing (NGS) and Sanger sequencing discovered c.2183A>T (p.Asn728Ile) missense variant in KIDINS220.The variant was absent in controls (i.e.gnomAD and Exome Sequencing Project) (PM2 criteria).Note that in silico prediction programs supported an uncertain significance of the variant (using VarSome, Lausanne, Vaud) [8].However, the patient's phenotype was highly suggestive of HSP with a monogenic etiology (PP4 criteria).We curated the Exome variant list for KIDINS220 from the exome sequencing project (see Appendices).For the variant c.2185G>A (p.A729T), the Polyphen2 (class: score) is listed as probably-damaging: 0.997 (in bold in the table in Appendices).Since this was adjacent to the variant found in our patient (c.2183A>T (p.N728I)), one would expect the variant in our patient to be probably pathogenic as well.Based on the abovementioned American College of Medical Genetics criteria [9] and caveats, one could suggest the likely pathogenicity of this variant.The other mutation discovered (CYP27A1 (c.546T>G, p.Ile182Met)) would not have fit the phenotypic description of the patient, and considering variant allele frequency, it was less likely to be contributive.Note though, although it seemed plausible that the case was sporadic, we were unable to perform NGS on the family members to provide clear evidence for it.
Initially, the patient's symptoms were managed with physical and occupational therapy.Baclofen was also used for spasticity.She was neurologically stable during a close follow-up visit; however, it was felt that she would require further titration of antispasmodics for the lower extremity spasticity.HSP is a heterogeneous group of monogenic progressive neurodegenerative disorders characterized by the involvement of corticospinal tract and dorsal columns [10].The prototypical presentation in the pure type involves slowly progressive spastic paraparesis, urinary incontinence, and minimal sensory symptoms.In the complex type, other nervous system manifestations including cognitive impairment, extrapyramidal involvement, peripheral neuropathy, optic neuropathy, retinal disease, seizures, and more pronounced sensory symptoms may be present.The genetic classification of HSP is based on the spastic paraplegia gene (SPG) designation.Table 1 characterizes HSP based on the mode of inheritance with some common subtypes highlighted; there is heterogeneity in terms of gene involvement and clinical presentation [10].References: [10,11] HSP: hereditary spastic paraplegia; AR: autosomal recessive; AD: autosomal dominant; SPG: spastic paraplegia gene

Mode of inheritance
Our patient was unique in having primarily pure HSP features associated with the KIDINS220 missense variant reported (c.2183A>T(p.Asn728Ile)) here which expands the HSP spectrum further.This is different from the prior KIDINS220 nonsense variants leading to SINO [6].Although we suggest likely pathogenicity of our variant, confirmation of pathogenicity would entail functional studies.One possible approach would be to induce our missense KIDINS220 variant in motor neurons (using Gal4/UAS) to look for spasms in zebrafish as performed previously [6].Additionally, our patient did not have any features of ventriculomegaly or iNPH as noted above [7].This warrants further investigation of the biology of KIDINS220.

Conclusions
We described a case of pure HSP with a likely pathogenic KIDINS220 variant.This case helps expand the HSP subtype spectrum and adds to the growing body of knowledge regarding the genetic heterogeneity of this condition.This provides opportunities for greater pathophysiological understanding and targeted molecular therapy.