Table 1.

Clinical description of patients carrying homozygous ADPRHL2 missense variants showing variable phenotypes.

IndividualA:II:1 (patient 1)A:II:2 (patient 2)B:II:1 (patient 3)
 GenderMMF
 Parental consanguinityReported negativeReported negative+
 Current age or age at death34 yr32 yra16 yra
 Circumstances of deathCardiac arrest/respiratory failureRespiratory failure
ADPRHL2 Mutation
 Genomic position (hg19)Chr1: 36558899T>GChr1: 36558899T>GChr1: 36554582G>T
 cDNANM_017825: c.1004T>GNM_017825: c.1004T>GNM_017825: c.77G>T
 Proteinp.Val335Glyp.Val335Glyp.Cys26Phe
Clinical features
 Age at onset13 yr15 yr15 mo
 Symptoms at onsetWalking instability and intermittent lateropulsionFatigue and instability during walkingFebrile seizures
 Psychomotor developmentNormalNormalNormal speech, moderate intellectual disability (6 yr)
 General developmentNormalNormalGrowth retardation for which growth hormones were supplied
 GaitWeakness of foot dorsiflexors, drop foot, and mild spasticityFoot dorsiflexor weakness, drop foot, mild spasticity, and instability; later also affected by fractureWeakness of foot dorsiflexors, drop foot
 Muscle atrophyModerate atrophy of distal third of upper and lower limbsModerate atrophy of distal upper and lower limbs and mild proximal atrophyModerate atrophy of intrinsic hand muscles (10 yr), mild atrophy of distal lower limbs
 Proximal strength upper limb555
 Distal strength upper limb42–42/5 to 4-/5
 Proximal strength lower limb555
 Distal strength lower limb1–21–34-/5 to 5/5
 Reflexes upper limbNormalDiminishedNormal
 Reflexes lower limbNormalDistally diminishedNormal
 Sensory involvementHypoesthesia in tip toes, deep position, and vibration sense severely diminished in lower legs and handsHypoesthesia and loss of vibration sense in legs-
 Seizure type-Myoclonic jerksFebrile seizures
 Cardiac featuresNormalNormalLeft ventricle hypertrophy and mitral insufficiency
 Other clinical featuresMotor tics in childhood, micrognathia, nystagmus, postural tremor, absent trunk hair, pes cavus, mild to moderately restrictive pulmonary function, and scoliosisNystagmus, postural tremor, mild dysarthria, pes cavus, hyperhidrosis, absent trunk hair, carpal tunnel surgery, and mixed restrictive/obstructive lung functionModerate scoliosis, growth retardation, pes cavus, and exostosis with confirmed causal EXT1 variant
Neurological examination
 EMGSevere axonal motor polyneuropathy and mild sensory involvementSevere axonal motor polyneuropathy and mild sensory involvementProfound axonal motor polyneuropathy, no sensory involvement
 Brain MRI (age performed)Normal (13 yr)Normal (26 yr)Normal (13 yr)
Mild white matter hyperintensity lesions (33 yr)
 EEGNormalMild nonspecific changes with intermittent bifrontal theta wavesSporadic epileptiform activity frontocentral localization
 Other genetic features--NM_000127.2 (EXT1): c.538_539delAG (p.Leu181Profs)
  • a Individual is deceased