Article Figures & Data
Figures
- Figure 1.
GFAP levels in CSF. GFAP levels (in ng/L) in CSF of AxD patients and control subjects are shown; data are presented as the mean ± 1 SD on a split linear scale for the y-axis. GFAP levels in samples from AxD patients are significantly elevated compared with those from control subjects. Each data point represents one individual (AxD patients: n = 6 males, 4 females; control subjects, n = 7 males, 5 females; Wilcoxon rank sum test, p < 0.001a).
- Figure 2.
GFAP levels in blood. GFAP levels (in ng/L) in blood of control subjects compared with AxD patients grouped by age of onset (infantile onset, 0-2; juvenile onset, >2-13; adult onset, >13). Each data point represents one individual. Horizontal bars indicate the mean, and the error bars indicate ±1 SD. The infantile group (Wilcoxcon rank sum test, p = 0.002b) and the juvenile group (Wilcoxon rank sum test, p = 0.025c) are significantly different than control subjects.
- Figure 3.
Within-subject comparison of GFAP levels in CSF and blood. GFAP levels in blood are shown as a function of the levels in CSF for the ten patients for whom both types of samples were available. CSF values were consistently higher than blood values. However, as indicated by the ages at collection as given in Table 1, the samples were not contemporaneous. No statistical analysis was performed due to the low number of samples.
Tables
Age (years) Sex Reason for LP 0.08 M Respiratory syncytial virus bronchiolitis 0.08 F Acute respiratory failure 0.12 F Acute life-threatening event 0.66 M Vomiting 2.16 F Gastrointestinal virus 2.25 M Lymphoma 3.08 M DiGeorge syndrome 3.75 F Acute lymphocytic leukemia/chemotherapy evaluation 3.92 M Acute lymphocytic leukemia/chemotherapy evaluation 4.08 M Acute lymphocytic leukemia/chemotherapy evaluation 4.33 M Acute lymphocytic leukemia/chemotherapy evaluation 5.25 M Acute lymphocytic leukemia/chemotherapy evaluation 5.33 M Acute lymphocytic leukemia 5.75 M Acute lymphocytic leukemia/chemotherapy evaluation 6.92 F Acute lymphocytic leukemia/chemotherapy evaluation 9.25 M Acute lymphocytic leukemia/chemotherapy evaluation 9.58 F Ehlers-Danlos syndrome, mental status change 12.33 M Acute lymphocytic leukemia/chemotherapy evaluation 14.16 F Acute lymphocytic leukemia/chemotherapy evaluation 14.75 F Acute lymphocytic leukemia/chemotherapy evaluation 15.33 F Idiopathic intracranial hypertension 16.66 M Acute lymphocytic leukemia/chemotherapy evaluation 17.33 M Acute lymphocytic leukemia/chemotherapy evaluation 19 M Acute lymphocytic leukemia/chemotherapy evaluation Deidentified control CSF samples are tabulated indicating sex and the clinical reason for LP. Age at collection is given in years. F, Female; M, male.
Patient no. Mutation Sex Age at illness onset (years) Age at sample collection (years) Death Reference CSF Blood 1 R70Q F 40.5 44.67 Patient 12 in Caroli et al. (2007) 2 N77S M 0.16 1.75 3 N77S F 1 3.26 4 N77S, S152L F 0.58 19.19 5 R79C M 0.5 17.28 20.84 Patient 6 in Li et al. (2005) 6 R79C M 0.25 6.20 Matarese and Renaud (2008) 7 R79C F 4* 4* 8 R79C F 0.5 2.02 9 R79G F 0.29 2.25 2.65 10 R79H F 0.58 6.27 7.11 11 R79H F 0.5 1.92 12 R79H F 1.25 10.51 13 R79H F 0 3.07 14 R79L M 0.5 4.65 4.65 15 R88C M 4 13.36 Patient 10 in Gorospe et al. (2002) 16 R88C M 0.75 2.24 17 R88C M 2 5.77 18 R88C M 10 15.78 17.87 19 R88C† F 10 40.95 Patient 3 in van der Knaap et al. (2006) 20 R88C† M 10 17.32 21.62 Patient 4 in van der Knaap et al. (2006) 21 R105W‡ F 6 15.74 22 L123P M 50 56.72 23 E207Q M 10.5 22.11 22.52 Patient 12 in Li et al. (2005)
Patient 7 in van der Knaap et al. (2005)24 L231H† M 50 64.88 Delnooz et al. (2008) 25 L231H† M NA 34.85 26 R239C M 0.5 2.50 27 R239C F 1.5 2.10 28 R239C F 7.00 9.20 29 R239C F 1.67 1.90 30 R239H F 0.29 0.72 1.14 31 R239H F 0 0.96 1.00 32 R239P M 2 23.85 23.85 Patient 1 in van der Knaap et al. (2005) 33 R239P M 1.5 3.25 34 S247P M 10 36.68 Patient A.II.d in Messing et al. (2012a) 35 R258P M 0 3.72 2.61 36 R270-A272del F <0.25 3.93 37 Q290E F 12 13.82 Patient 1 in Barreau et al. (2011) 38 E362Q F 5 20.52 39 E371Q M <1 9.78 40 E373A F 34 36.60 41 E374G F 0 1.91 12.82 Patient 40 in Li et al. (2005) 42 S398F F 45 45.59 45.84 43 S398Y F 51* 56.67 Patient 9 in Pareyson et al. (2008) and Farina et al. (2008) 44 M415I† F 40 52.22 de Souza Rezende et al. (2012) 45 M415I†, D157N§ F 4 19.46 de Souza Rezende et al. (2012) 46 R416W M 14 31.47 31.19 33.63 47 R416W M 13 31.68 Patient 3 in Pareyson et al. (2008) and
Farina et al. (2008)48 R416W M 6 8.14 49 R416W F 16 25.93 50 Q426L F 30 44.15 44.15 Patient C.II.1 in Messing et al. (2012a) Information regarding each patient who contributed blood and/or CSF samples is shown, including gender, GFAP mutation, age of illness onset, age at sample collection, and age at death (if relevant), and sorted by GFAP mutation. For some patients, the age of illness onset was estimated (*) or the patient was asymptomatic but had a familial history of AxD (NA). All ages are given in years. References to prior publications containing additional clinical details about particular patients are also given, if available. F, Female; M, male.
↵* Age of onset was estimated.
↵† Parent–child duos are shown together on consecutive lines (19-20, 24-25, and 44-45).
↵‡ The pathogenicity of the R105 mutation is uncertain.
↵§ The D157N mutation is considered a benign variant, but its impact in a compound heterozygote is not known.
Patient no. Mutation Sex GFAP levels
(ng/L)Age at illness onset
(years)Duration of illness
(years)CSF Blood CSF Blood 1 R70Q F 64 40.5 4.17 2 N77S M 1640 0.16 1.59 3 N77S F 802 1 2.26 4 N77S, S152L F 480 0.58 18.61 5 R79C M 5803 256 0.5 16.78 20.34 6 R79C M 1864 0.25 5.95 7 R79C F 3489 3.9* 0.10* 8 R79C F 426 0.5 1.52 9 R79G F 1201 0.29 1.96 10 R79H F 14290 1154 0.58 5.69 6.53 11 R79H F 255 0.5 1.42 12 R79H F 302 1.25 9.26 13 R79H F 572 0 3.07 14 R79L M 20355 1925 0.5 4.15 4.15 15 R88C M 238 4 9.36 16 R88C M 46 0.75 1.49 17 R88C M 329 2 3.77 18 R88C M 5095 132 10 5.78 7.87 19 R88C† F 1068 10 30.95 20 R88C M 2493 122 10 7.32 11.62 21 R105W‡ F 105 6 9.74 22 L123P M 219 50 6.72 23 E207Q M 751 10.5 11.61 24 L231H† M 95 50 14.88 25 L231H M 243 N/A N/A 26 R239C M 1007 0.5 2.00 27 R239C F 791 1.5 0.60 28 R239C F 504 7 2.20 29 R239C F 237 1.67 0.23 30 R239H F 169 0.29 0.43 31 R239H F 711 0 0.96 32 R239P M 24272 713 2 21.85 21.85 33 R239P M 461 1.5 1.75 34 S247P M 248 10 26.68 35 R258P M 2721 750 0 2.61 36 R270-A272del F 1314 0.25* 3.68* 37 Q290E F 446 12 1.82 38 E362Q F 322 5 15.52 39 E371Q M 704 0.9* 8.88* 40 E373A F 187 34 2.60 41 E374G F 387 0 1.91 42 S398F F 1402 505 45 0.59 0.84 43 S398Y F 112 51* 5.67* 44 M415I† F 46 40 12.22 45 M415I, D157N§ F 571 4 15.46 46 R416W M 2478 62 14 17.47 17.19 47 R416W M 545 13 18.68 48 R416W M 712 6 2.14 49 R416W F 64 16 9.93 50 Q426L F 1749 114 30 14.15 14.15 GFAP concentrations (in ng/L) in CSF and blood of individual AxD patients. Patient 25 was asymptomatic at the time of collection. Duration of illness is defined as the age at sample collection less the age at illness onset, using the values shown in Table 2. Parent–child duos are shown together (19-20, 24-25, and 44-45), as in Table 2. All blood samples are plasma, except for three (9, 16, and 50), which are serum. N/A, not applicable.
↵* Age at illness onset and duration of illness were estimated.
↵† Parent–child duos are shown together on consecutive lines (19-20, 24-25, and 44-45).
↵‡ The pathogenicity of the R105 mutation is uncertain.
↵§ The D157N mutation is considered a benign variant, but its impact in a compound heterozygote is not known.
Patient no. Mutation Sex Onset First symptom Highest cognitive Highest motor Main deterioration Age at loss of unassisted walking 1 R70Q F 40.5 Ataxia Normal Walks without support Gait No 2 N77S M 0.16 Frequent arching, seizures Severe ID None at all Severe spasticity, intractable seizures N/A 3 N77S F 1 Speech and motor delay Moderate ID Walks without support, but wide-based gait ND ND 4 N77S, S152L F 0.58 Seizures Normal Walks with support Motor and language deterioration Yet to walk without support 5 R79C M 0.5 Motor delay Mild ID Walks without support Spastic tetraparesis, cognitive problems 14 years 6 R79C M 0.25 Macrocephaly, developmental delay Normal Walks without support None No 7 R79C F 4* ND ND ND ND ND 8 R79C F 0.5 Developmental delays in speech, walking, hypotonia Mild–moderate ID Standing Facial droop after concussion Yet to walk without support 9 R79G F 0.29 Seizures Severe ID Sitting without support Loss of sitting Never walked without support 10 R79H F 0.58 Seizure Mild ID Walks without support Ataxia ND 11 R79H F 0.5 Arching back and eye rolling upward Normal Walks with support Seizures Yet to walk without support 12 R79H F 1.25 Seizure Moderate ID Walks without support Motor skills, cognition No 13 R79H F 0 Hypotonia Severe ID Reaching for objects N/A N/A 14 R79L M 0.5 Progressive macrocephaly; slowed development Moderate ID Walks a few steps without support None No 15 R88C M 4 Short stature, followed by slowed cognitive development Mild ID Walks without support Progressive dysarthria, cognitive delay No 16 R88C M 0.75 Macrocephaly, developmental delay Mild ID Walks with support None Yet to walk without support 17 R88C M 2 Seizure Mild ID Walks without support Motor decline, seizures, bulbar problems 5 years 18 R88C M 10 Deterioration in academic skills Mild ID Walks without support Neurocognitive decline and spasticity No 19 R88C† F 10 Vomiting, anorexia Normal Walks without support Scoliosis, gait 30 years 20 R88C† M 10 Incoordination Normal Walks without support Scoliosis, gait, some cognitive decline No 21 R105W‡ F 6 Memory, math and spelling, behavior Mild ID Walks without support None No 22 L123P M 50 Progressive gait problems, inbalance Normal Walks without support Bulbar dysfunction ND 23 E207Q M 10.5 Scoliosis, followed by abnormal gait, fatigue, and weakness Normal Walks without support Difficulty walking, urinary incontinence 22 years 24 L231H† M 50 Ataxia Normal Walks without support Ataxia 63 years 25 L231H† M na None Normal Walks without support None No 26 R239C M 0.5 Macrocephaly, developmental delay Severe ID Standing with support Swallowing, tone, hydrocephalus Yet to walk without support 27 R239C F 1.5 Hypotonia, gross motor delay, macrocephaly Severe ID Walks with support Failure to thrive, emesis, but no regression Yet to walk without support 28 R239C F 7 Choking episodes Mild ID Walks without support Gait deterioration, dysarthria, urinary incontinence No 29 R239C F 1.67 Intermittent ataxia Normal Walks without support Occasional unsteadiness No 30 R239H F 0.29 Vomiting, hypotonia, minimal development Only social contact None at all Progressive bulbar dysfunction Never walked without support 31 R239H F 0 Hydrocephalus, minimal development Severe ID None N/A N/A 32 R239P M 2 Vomiting, deterioration of gait Moderate ID Walks without support Mild deterioration of gait No 33 R239P M 1.5 Speech and motor delay Mild ID Walks with support None Yet to walk without support 34 S247P M 10 Severe morning emesis Normal Walks without support Sleep apnea No 35 R258P M 0 Macrocephaly, hypotonia Mild–moderate ID Walks without support Seizures, dysarthria, ataxia No 36 R270-A272del F <0.25 Motor delay, macrocephaly Severe ID Very limited N/A N/A 37 Q290E F 12 Worsening migraines Normal Walks without support No No 38 E362Q F 5 Seizures, ataxia, rigidity Normal Normal Dysarthria, short-term memory, executive function No 39 E371Q M <1 Motor delay Mild ID Walks without support Neurocognitive delay No 40 E373A F 34 Numbness, burning sensation Normal Normal gait Fatigue, balance, bladder No 41 E374G F 0 Hypotonia, lack of development Moderate ID Walks with support Lost all skills, frequent vomiting Never walked without support 42 S398F F 45 Dysarthria Normal Walks without support Ataxia, palatal tremor No 43 S398Y F 51* MRI after subarachnoid hemorrhage at 51 years, mild urinary urgency at 56 years Normal Walks without support Urinary urge-incontinence, unsteadiness No 44 M415I† F 40 Balance difficulties Normal Walks without support Speech, urinary, headache No 45 M415I†, D157N§ F 4 Ataxia Normal Walks without support Urinary retention, bulbar dysfunction ∼8 years 46 R416W M 14 Behavior and gait problems; single seizure Low normal Walks without support Ataxia, dysarthria, behavior 18 years 47 R416W M 13 Dysarthria, dysphagia Normal Walks without support Cognitive impairment, neurogenic bladder, obstructive sleep apnea, palatal tremor 29 years 48 R416W M 6 Febrile seizure Low normal Walks without support Mild proximal weakness No 49 R416W F 16 Balance, bladder Normal Walks without support Balance coordination, weakness, swallowing, hallucinations No 50 Q426L F 30 Urinary incontinence, neurogenic bladder Normal Normal Exercise intolerance 45 Information regarding each patient is shown including age of onset, nature of first symptom, highest cognitive level, highest motor level, major deterioration (if any), and age at loss of unassisted walking (if it occurred). All ages are given in years. ID, Intellectual disability; N/A, not applicable; ND, not determined or unknown; F, female; M, male.
↵* Age of onset was estimated.
↵† Parent-child duos are shown together on consecutive lines (19-20, 24-25, and 44-45).
↵‡ The pathogenicity of the R105 mutation is uncertain.
↵§ The D157N mutation is considered a benign variant, but its impact in a compound heterozygote is not known.
Data structure Type of test 95% CI a Quantitative scale, non-normally distributed Wilcoxon rank sum test 1876–14226 ng/L b Quantitative scale, non-normally distributed Wilcoxon rank sum test 191–1015 ng/L c Quantitative scale, non-normally distributed Wilcoxon rank sum test 40–563 ng/L d Quantitative scale, non-normally distributed Wilcoxon rank sum test 250–710 ng/L e Quantitative scale, non-normally distributed Wilcoxon rank sum test −110–381 ng/L
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