Table 1
Clinical, electrophysiological, radiological, and genetic findings of patients with FA2H-related neurodegeneration in our cohort.
| VARIABLES | CASE-1 | CASE-2 | CASE-3 | CASE-4 | CASE-5 | CASE-6 | CASE-7 | CASE-8 |
|---|---|---|---|---|---|---|---|---|
| Demographics and history | ||||||||
| Age/AAO/Gender | 10y/7y/F | 29y/10y/M | 8y/4y/F | 10y/4y/F | 7y/5y/F | 8y/7y/F | 15y/5y/F | 7y/6y/F |
| Consanguinity/FH | Yes/No | Yes/No | Yes/No | Yes/No | Yes/No | No/Yes | Yes/No | No/No |
| DD | No | No | No | Mild – Motor | Mild – motor | No | No | |
| Presenting symptom | Difficulty walking, and speaking | Difficulty walking, speaking, and poor scholastic performance | Difficulty walking and speaking | Difficulty walking and speaking, and hand incoordination | Difficulty walking | Difficulty walking | Difficulty walking, speaking, and writing difficulty | Difficulty walking, speaking, and hand incoordination |
| Examination | ||||||||
| Cognition | Normal | Impaired | Impaired | Normal | Normal | Normal | Impaired | Normal |
| Eye movements | Saccadic pursuits, hypermetric saccade | Slow saccades, broken pursuit, exotropia | Normal | Upgaze restriction, | Normal | GEN | GEN | GEN |
| Fundus | Mild temporal pallor | Normal | Normal | Normal | Mild temporal pallor | Normal | Normal | Normal |
| Speech | Spastic-ataxic | Spastic | Ataxic | Spastic-Ataxic | Spastic | Normal | Spastic | Spastic-Ataxic |
| Tone | Spastic in all 4 limbs | Spastic in all 4 limbs | Spastic in all 4 limbs | Spastic in legs | Spastic in legs | Spastic in all 4 limbs | Spastic in all 4 limbs | Spastic in all 4 limbs |
| Power | Normal | Normal | Normal | Normal | Normal | Normal | Lower limb | Normal |
| DTR | Brisk in all 4 limbs | Brisk in all 4 limbs | Brisk in all 4 limbs | Brisk in all 4 limbs | Brisk in all 4 limbs | Brisk in all 4 limbs | Brisk in all 4 limbs | Brisk in all 4 limbs |
| Plantar | Extensor bilaterally | Extensor bilaterally | Extensor bilaterally | Extensor bilaterally | Extensor bilaterally | Extensor bilaterally | Extensor bilaterally | Extensor bilaterally |
| Cerebellar | Ataxia | Normal | Ataxia | Ataxia | Normal | Normal | Ataxia | Ataxia |
| Gait | Spastic ataxic | Wheelchair bound | Spastic ataxic | Spastic ataxia | Spastic | Spastic | Spastic-ataxic | Spastic-ataxic |
| Dystonia | Distal limbs | None | None | None | None | None | None | None |
| Ambulation | Without support | Wheelchair bound | Without support | With support | With support | Without support | With support | Without support |
| Pes-cavus | Present | Present | Absent | Absent | Absent | Absent | Absent | Absent |
| Contracture | Ankle | Hamstring, ankle | Ankle | Ankle | None | None | Ankle | Absent |
| Investigations | ||||||||
| Blood investigations# | Normal | Normal | Normal | Normal | Normal | Normal | Normal | Normal |
| NCS | Normal | Sensory axonal | NA | NA | Normal | NA | NA | Normal |
| VEP | R-126 µs/L-132 µs | NA | NA | L-133.8 µs/R-127.2 µs | NA | NA | NA | Normal |
| BAER | Normal | NA | NA | Normal | Normal | NA | NA | Normal |
| SSEP | Normal | Normal | NA | Normal | Normal | NA | NA | Normal |
| MRI Brain | ||||||||
| Callosal atrophy | Present | Present | Present | Present | Present | Present | Present | Present |
| Optic atrophy | Present | Present | Absent | Present | Present | Absent | Absent | Absent |
| Cerebellar atrophy | Present | Present | Present | Present | Present | Present | Present | Present |
| PVWMH | Present | Present | Present | Present | Present | Present | Present | Present |
| GPi hypointensity | Present (T2 & SWI) | Present (T2 & SWI) | Absent | Present (T2 & SWI) | Present (T2) | NA | NA | Present (T2) |
| Variants identified in the FA2H (ENST00000219368) | ||||||||
| Zygosity | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous |
| Exon | Exon-1 | Exon-1 | Exon-4 | Exon-1 | Exon-3 | Exon-5 | Exon-1 | Exon-1 |
| Nucleotide change | c.200_202del | c.130C>A | c.536delT | c.83G>C | c.379C>T | c.703C>T | c.200_202del | c.86_97dup |
| Amino acid change | p.His67del | p.Pro44Thr | p.Leu179ArgfsTer62 | p.Arg28Pro | p.Arg127Ter | p.Arg235Cys | p.His67del | p.Arg29_Arg32dup |
| Consequence | In-frame deletion | Missense | Frameshift, truncation | Missense | Nonsense | Missense | In-frame deletion | In-frame duplication |
| ACMG classification | Likely pathogenic | Likely pathogenic | Pathogenic | Likely pathogenic | Pathogenic | Likely pathogenic | Likely pathogenic | Likely Pathogenic |
| PM1,2,4,PP3 | PM1,2,5,PP2,3 | PVS1,PM2,PP3 | PM1,2,PP2,3 | PVS1,PM2,PP3,5 | PM2,3,PP3,4,5 | PM1,2,4,PP3 | PM1,2,4,PP4 | |
| Novel variant | Yes | Yes | Yes | Yes | No | No | Yes | Yes |
| CADD | NA | 32 | NA | 30 | NA | 32 | NA | NA |
| REVEL | NA | 0.9 | NA | 0.66 | NA | 0.85 | NA | NA |
[i] #: Blood investigations contain complete blood count, renal function test, liver function test, thyroid function test, vitamin B12, homocysteine, and tandem Mass spectroscopy.
AAO: Age at onset; BAER: Brainstem auditory evoked potential; CADD: Combined Annotation Dependent Depletion; DTR: Deep tendon reflexes; F: Female; FH: Family history; GEN: Gaze-evoked nystagmus; GPi: Globus pallidi interna; M: Male; MRI: Magnetic resonance imaging; NA: Not available; NCS: Nerve conduction study; PVWMH: Peri-ventricular white matter hyperintensity; REVEL: Rare Exome Variant Ensemble Learner; SSEP: Somatosensory evoked potential; SWI: Susceptibility weighted imaging; VEP: Visual evoked potentials; y: years.
Figure 1
Magnetic resonance imaging of the cohort. T2, FLAIR, and SWI sequences of the MRI brain of the patients demonstrating callosal atrophy, cerebellar atrophy, and periventricular white matter hyperintensity in all, GPi hypointensity on T2 sequences in Cases 1, 2, 4, 5, and 8, and on SWI sequences in Cases 1, 2, and 4. Snapshots of the MRI of Case 7 were not available. FLAIR: Fluid attenuated inversion recovery; GPi: Globus pallidi interna; MRI: Magnetic resonance imaging; SWI: Susceptibility weighted imaging.
Figure 2
Cartoon depicting the details and location of the variants identified in the cohort on the FA2H.