the now 17-year - old right - handed male proband was referred for neurological evaluation at age 13 years , with a 3-year history of slowly progressive distal symmetric upper and lower limb weakness , distal intrinsic hand and foot muscle wasting , and distal joint deformities .
he was born to first cousin parents ( maternal grandfather and paternal grandmother are siblings ) who emigrated from afghanistan to canada during pregnancy , which was otherwise unremarkable .
the mother is in good health , the father s history is unavailable to us , and the proband has a healthy half - sister born to a different mother .
delivery was spontaneously at term , with good apgar scores and normal growth parameters ; tone was unremarkable , and orthopedic manifestations were absent .
investigation of excessive bruising at age 4 years led to the diagnosis of type 3 von willebrand disease ( homozygous c.5557c > t / p.arg1853x variant in vwf gene ) , requiring intermittent medical treatment .
there was no history of intracranial bleeding nor significant trauma to the head , neck , or spine . aside from mild asthma , requiring occasional use of inhalers , he was in good health .
early neurodevelopmental milestones were normal : he crawled and sat without support at 6 months , walked independently at age 1 year , and spoke in 2-word phrases by age 2 years .
his school performance was age appropriate ; he was able to write , run , and play sports .
however , by age 10 years , he was often noted to trip and fall while running . by age 13 years , he was no longer able to run ; his hands and feet were weak , with claw deformities of fingers and toes ( figure 1b and c ) and with impeding skills such as writing and using utensils .
there was no history of cognitive regression , seizures , impairment of vision / hearing , diplopia , facial weakness / numbness , dysphagia / dysarthria , upper / lower limb paresthesias or sensory loss , significant cervical , thoracic , lumbosacral , or limb pain , or impairment of bowel / bladder sphincter control .
d , family pedigree and sanger resequencing results . the mother is a carrier , and the index is homozygous for the variant in sigmar1
. physical examination at age 13 years ( figure 1b and c ) revealed normal mental status and normal cranial nerves .
triceps reflexes were present , but biceps and brachioradialis reflexes were absent in both upper limbs ; patellar and ankle reflexes were diminished bilaterally , without ankle clonus .
proximal upper and lower limb bulk and power was normal in all the 4 limbs .
however , there was marked symmetric weakness of distal small intrinsic muscles of both hands and feet , with wasting of thenar and hypothenar eminences bilaterally ; no fasciculations were noted . at rest , the thumbs were held adducted and all the 4 fingers were clawed .
gait was wide based ; he was unable to walk on his heels or toes .
sensory examination ( light touch , vibration , proprioception , temperature , and pinprick ) was normal , proximally and distally , in all the 4 limbs . at age 13 and 16 years
, motor nerve conduction studies ( table 1 ) showed diffusely and markedly reduced amplitudes , with mild slowing of conduction velocities and normal distal latencies .
needle electromyography studies ( right extensor digitorum communis , right first dorsal interosseous , right tibialis posterior , and right vastus lateralis ) showed markedly large amplitudes of motor unit action potentials , most pronounced in the right tibialis anterior where motor unit action potentials measured up to 10 mv .
comparison of conduction study results of our patient to those reported by li et al . 
 

conduction studies were done only for 1 patient in the study of li et al . 
 

because his inability to move his right thumb or extend his fingers compromised his ability to write , he underwent right - hand tendon transfer surgery at age 14 years .
postoperatively , he noted not only modest improvement in right thumb motion but also intermittent right hand pain and paresthesias . at age 17.5 years , he underwent repeat neurological evaluation , which was unchanged .
he continued to attend a regular school program , but he was falling behind academically most likely due to his physical disabilities .
no regression or signs of an evolving cognitive have been observed ; formal neurocognitive testing has not been performed due to logistical issues .
he complained of ongoing intermittent cramping and pain in his right hand , provoked by prolonged handwriting with postsurgical paresthesias in dorsum and ulnar side of the hand ; his left hand had normal sensation and was pain free .
he noted intermittent pain in feet and ankles after prolonged walking or standing but denied paresthesias or impairment of sensation in lower limbs .
magnetic resonance imaging of the spine showed mild to moderate lumbar spinal stenosis at age 14 years , with anterior  posterior dimension of the spinal canal measuring 9 mm at l4 ; the stenosis is deemed unrelated to the sigmar1 deficiency .
there was no evidence of chiari malformation , syrinx , or spinal cord pathology ; the spinal cord ends with the inferior border at l1 .
molecular analysis of smn and pmp22 revealed no pathogenic variants , deletions , or duplications .
chromosome microarray analysis ( cytoscan hd ; affymetrix , santa barbara , ca ) showed large regions of homozygosity ( 22 identified regions using a threshold of homozygosity regions > 4 mb ) but was otherwise unremarkable .
after enrollment of the family within the tidex gene discovery project ( university of british columbia institutional review board approval h12 - 00067 ) , whole exome sequencing was performed for the proband and his unaffected mother using the agilent sureselect kit and illumina hiseq 2000 ( perkin - elmer , santa clara , ca ) .
rare variants ( those with minor allele frequency < 0.01 ) were assessed for predicted impact on protein function and screened under multiple inheritance models . given the consanguinity , the variants were prioritized for homozygous - recessive inheritance and filtered to focus on regions of homozygosity .
whole exome sequencing revealed 49 recessive candidate variants ( 4 hemizygous , 33 homozygous , and 12 compound heterozygous ) .
of those , the homozygous c.151 + 1 g > t variant in sigmar1 ( located in a 8.5 mb long region of homozygosity spanning chromosome 9p21.1-p13.2 ) was considered a functional candidate based on the ( 1 ) report by li et al of the same recessive sigmar1 variant in a family with highly overlapping phenotypes ; ( 2 ) rarity of the variant  aside from the recent report , the variant has not been observed in dbsnp ( release 142 ) , exome aggregation consortium ( v.0.3 ) , national heart , lung , and blood institute exome sequencing project ( v.0.0.30 ) , or our in - house database of more than 350 whole exome / whole genome sequencing results ; and ( 3 ) high deleteriousness ( 26.7 ) predicted by combined annotation - dependent depletion .
sanger resequencing confirmed that the proband was homozygous for the variant , and the mother was heterozygous for the same variant ( figure 1d ) ; the father s dna was unavailable .
in summary , this report further validates causality of the c.151 + 1g > t sigmar1 variant for a distal hereditary motor axonal neuropathy affecting the upper and lower extremities ; the phenotypic presentation is highly similar to the patients first reported by li et al .
interestingly , the first reported patients ( in their 30 seconds at the time of the report ) and our patient present a similar pattern of disease progression : onset of symptoms at age 9 to 13 years , subsequent progression during growth spurt , and stabilization by early adulthood ( age 16 - 20 years ) .
the authors speculate a mechanistic disease pathophysiology : the ability of motor axons to remain viable was limited while being required to elongate .
this hypothesis is supported by a recent report by tsai et al , which describes the role of sigmar1 protein ( sigma-1 receptor ) in regulating axon elongation and tau phosphorylation .
the authors propose that the longest anterior horn cell motor axons are most vulnerable , explaining the neurodegenerative symptoms during the growth spurt .
in addition to distal hereditary motor neuropathy , sigmar1 has been tied to other neurodegenerative phenotypes , such as juvenile amyotrophic lateral sclerosis .
a recent report of the sigmar1 knockout mice is consistent with the human phenotypes described : the mice displayed motor function defects , decreased muscle strength , progressive denervation of neuromuscular junctions in fast - twitch tibialis anterior muscle , and small progressive motor neuron death in the lumbar spinal cord . 
 
another notable finding in our case is the presence of 2 different genetic defects ( in vwf and sigmar1 ) , accounting for the proband s hematological and neurological features .
the chance of dual genetic diagnoses increases with consanguinity , but such diagnoses have also been reported in offspring of unrelated parents , emphasizing the importance of thorough bioinformatics interpretations of whole exome sequencing data in the context of the patients phenotype .
the authors conclude that the sigmar1 deficiency should be added to the differential diagnosis of distal hereditary motor neuropathies .
further research including identification of other affected individuals with follow - up into adulthood  with repeat electrophysiological studies , as planned for our patient 
is needed to confirm the favorable prognosis ( stabilization during early adulthood ) of the c.151 + 1g > t variant , including the contribution of other sigmar1 variants to distal hereditary motor neuropathy - related phenotypes .
 distal hereditary motor neuropathies represent a group of rare genetic disorders characterized by progressive distal motor weakness without sensory loss . their genetic heterogeneity is high and thus eligible for diagnostic whole exome sequencing . 
 the authors report successful application of whole exome sequencing in diagnosing a second consanguineous family with distal hereditary motor neuropathy due to a homozygous c.151 + 1g > t variant in sigmar1 . 
 this variant was recently proposed as causal for the same condition in a consanguineous chinese family . 
 compared to this family , the afghan ethnic origin of our patient is distinct , yet the features are identical , validating the sigmar1 deficiency phenotype : progressive muscle wasting / weakness in lower and upper limbs without sensory loss . 
 rapid disease progression during adolescent growth is similar and may be due to sigmar1 s role in regulating axon elongation and tau phosphorylation . finally , the authors conclude that sigmar1 deficiency should be added to the differential diagnosis of distal hereditary motor neuropathies . 
Case Summary
Discussion
Supplementary Material