Table 3 Responses to Likert scale questions

Please indicate symptoms that paediatric patients (aged < 18 years old) present with, prior to a CTX diagnosis*

Chronic diarrhoea

Agreement

90

–

Round 1

Bilateral juvenile cataracts

Agreement

90

–

Round 1

Mental retardation (e.g. learning difficulties)^†

Agreement

100

–

Round 1

Please indicate symptoms that adult patients (aged ≥ 18 years old) present with, prior to a CTX diagnosis*

Infantile-onset diarrhoea

Agreement

70

–

Round 1

Childhood-onset cataracts

Agreement

90

–

Round 1

Tendon xanthomas

Agreement

90

–

Round 1

Psychiatric symptoms

Agreement

90

–

Round 1

Peripheral neuropathy

Agreement

70

–

Round 1

Cerebellar signs

Agreement

100

–

Round 1

Pyramidal signs

Agreement

90

–

Round 1

All patients have elevated levels of serum cholestanol at the time of diagnosis

Agreement

100

–

Round 1

Brain MRI should be performed at the diagnosis stage as they can contribute to the diagnosis of CTX by revealing abnormally increased or decreased signals with characteristics distribution, but also to exclude other conditions

Agreement

70

–

Round 1

Measurement of serum cholestanol levels is the diagnostic marker of choice for CTX

Agreement

100

–

Round 1

Movement disorders can be considered as late CTX manifestations, however, CTX should be considered in the differential diagnosis of movement disorders, particularly in case of an early onset and when associated with other neurological features and/or with systemic features

Agreement

70

–

Round 1

DBS testing is the optimal method for screening of CTX in newborns

Agreement

71

3

Round 1

CDCA is a lifetime replacement therapy

Agreement

100

–

Round 1

The pathophysiological process in CTX patients may be reversed by CDCA, especially if treatment is initiated early in the disease process

Agreement

100

–

Round 1

Transcranial magnetic stimulation (TMS) is a useful tool for evaluating improvements in pyramidal function in patients receiving CDCA

Disagreement

71

3

Round 1

Treatment adherence can be improved by providing CTX patients with support and intensive education

Agreement

90

–

Round 1

Pre-marital genetic counselling should be recommended to high-risk populations e.g. patients of Israeli or Moroccan origin

Agreement

75

2

Round 1

Please indicate which of the below therapy options improves/stabilises prognosis in the majority of CTX patients

CDCA alone

Agreement

100

–

Round 1

CDCA and HMG-CoA reductase inhibitor

Agreement

78

1

Round 2

LDL apheresis

Disagreement

71

3

Round 2

Cholic acid alone

Consensus not reached

Agree (33) Disagree (50)

3

Round 3

Cholic acid and HMG-CoA reductase inhibitor

Consensus not reached

Agree (20) Disagree (60)

4

Round 3

Reducing plasma cholestanol concentrations slows down the progression of CTX

Agreement

70

–

Round 1

CTX patients who start treatment after significant neurological pathology is established, have a worse prognosis compared to patients who started treatment as early as possible

Agreement

100

–

Round 1

CTX patients showing MRI evidence of cerebellar vacuolation should be monitored more strictly over time as it is considered a prognostic marker

Agreement

88

2

Round 1

During the early stages of treatment, paediatric patients should be monitored for the types of symptoms listed below 1–2 times per year

Central and peripheral nervous system

Agreement

100

1

Round 2

Ocular system

Agreement

78

1

Round 2

Enterohepatic system

Agreement

89

1

Round 2

Cognitive performance (e.g. learning difficulties)

Agreement

100

1

Round 2

Cardiovascular system

Consensus not reached

Agree (44) Disagree (33)

–

Round 3

Skeletal system

Consensus not reached

Agree (67) Disagree (0)

–

Round 3

Pulmonary system

Consensus not reached

Agree (33) Disagree (11)

–

Round 3

During the early stages of treatment, adult patients should be monitored for the types of symptoms listed below once per year

Central and peripheral nervous system

Agreement

100

–

Round 2

Ocular system

Agreement

70

–

Round 2

Cardiovascular system

Agreement

70

–

Round 2

Skeletal system

Agreement

70

–

Round 2

Enterohepatic system

Agreement

80

–

Round 2

Cognitive performance (e.g. learning difficulties)

Agreement

100

–

Round 2

During the early stages of treatment, adult patients should be monitored for symptoms in the pulmonary system once per year

Consensus not reached

Agree (38) Disagree (13)

1

Round 3

Paediatric patients should undergo the types of tests listed below 1–2 times per year

Cholestanol plasma concentration

Agreement

78

1

Round 2

Liver function tests

Agreement

78

1

Round 2

Paediatric patients should undergo neurologic (and if necessary neuropsychologic evaluation) testing/examination twice per year

Agreement

78

1

Round 2

Adult patients should undergo the types of tests/examinations listed below once per year

Cholestanol plasma concentration

Agreement

90

–

Round 2

Neurologic (and if necessary neuropsychologic evaluation)

Agreement

100

–

Round 2

Liver function tests

Agreement

90

–

Round 2

Urinary bile alcohol concentration

Consensus not reached

Agree (43) Disagree (14)

2

Round 3

Brain MRI

Consensus not reached

Agree (22) Disagree (33)

–

Round 3

The following healthcare professionals are important in the diagnosis of paediatric patients with CTX^‡

Neurologist

Agreement

100

1

Round 2

Paediatrician/Metabolic specialist

Agreement

89

1

Round 2

Geneticist

Agreement

78

1

Round 2

Ophthalmologist

Agreement

100

–

Round 3

Neuroradiologist

Consensus not reached

Agree (44) Disagree (22)

–

Round 3

Psychiatrist

Consensus not reached

Agree (33) Disagree (0)

–

Round 3

Orthopaedic surgeon

Consensus not reached

Agree (22) Disagree (33)

–

Round 3

Endocrinologist

Consensus not reached

Agree (11) Disagree (67)

–

Round 3

Gastroenterologist

Consensus not reached

Agree (33) Disagree (11)

–

Round 3

The following healthcare professionals are important in the diagnosis of adult patients with CTX^‡

Neurologist

Agreement

100

–

Round 2

Metabolic specialist

Agreement

80

–

Round 2

Geneticist

Agreement

80

–

Round 2

Ophthalmologist

Agreement

78

–

Round 3

Neuroradiologist

Consensus not reached

Agree (56) Disagree (22)

–

Round 3

Psychiatrist

Consensus not reached

Agree (67) Disagree (0)

–

Round 3

Orthopaedic surgeon

Consensus not reached

Agree (22) Disagree (33)

–

Round 3

Endocrinologist

Consensus not reached

Agree (22) Disagree (56)

–

Round 3

Gastroenterologist

Consensus not reached

Agree (33) Disagree (22)

–

Round 3

Cardiologist

Consensus not reached

Agree (22) Disagree (56)

–

Round 3

The following healthcare professionals should be involved in prescribing treatment to paediatric patients^‡

Neurologist

Agreement

78

1

Round 2

Neuroradiologist

Disagreement

78

1

Round 2

Paediatrician/Metabolic specialist

Agreement

89

1

Round 2

Family doctor

Disagreement

78

1

Round 2

Endocrinologist

Consensus not reached

Agree (11) Disagree (67)

–

Round 3

Psychiatrist

Consensus not reached

Agree (22) Disagree (44)

–

Round 3

The following healthcare professionals should be involved in prescribing treatment to adult patients with CTX^‡

Neurologist

Agreement

100

–

Round 2

Neuroradiologist

Disagreement

80

–

Round 2

Metabolic specialist

Agreement

80

–

Round 2

Cardiologist

Disagreement

70

–

Round 2

Family doctor

Disagreement

70

–

Round 2

Ophthalmologist

Disagreement

70

–

Round 2

Endocrinologist

Disagreement

78

–

Round 3

Gastroenterologist

Consensus not reached

Agree (0) Disagree (67)

–

Round 3

Psychiatrist

Consensus not reached

Agree (22) Disagree (44)

–

Round 3

The following healthcare professionals should be involved in the follow-up of paediatric patients with CTX^‡

Neurologist

Agreement

89

1

Round 2

Paediatrician/Metabolic specialist

Agreement

100

1

Round 2

Ophthalmologist

Agreement

100

–

Round 3

Neuroradiologist

Consensus not reached

Agree (33) Disagree (11)

–

Round 3

Family doctor

Consensus not reached

Agree (56) Disagree (0)

–

Round 3

Endocrinologist

Consensus not reached

Agree (22) Disagree (33)

–

Round 3

Gastroenterologist

Consensus not reached

Agree (22) Disagree (11)

–

Round 3

Psychiatrist

Consensus not reached

Agree (44) Disagree (11)

–

Round 3

The following healthcare professionals should be involved in the follow-up of adult patients with CTX^‡

Neurologist

Agreement

100

–

Round 2

Ophthalmologist

Agreement

70

–

Round 2

Metabolic specialist

Agreement

80

–

Round 2

Neuroradiologist

Consensus not reached

Agree (33) Disagree (22)

–

Round 3

Cardiologist

Consensus not reached

Agree (33) Disagree (0)

–

Round 3

Gastroenterologist

Consensus not reached

Agree (33) Disagree (22)

–

Round 3

Family doctor

Consensus not reached

Agree (56) Disagree (0)

–

Round 3

Endocrinologist

Consensus not reached

Agree (33) Disagree (22)

–

Round 3

Psychiatrist

Consensus not reached

Agree (56) Disagree (11)

–

Round 3

A specialist CTX centre/department should be visited once per year by:

Adult patients with CTX

Agreement

100

–

Round 2

Paediatric patients with CTX

Agreement

89

1

Round 2

A local CTX centre/department should be visited twice per year by:

Adult patients with CTX

Agreement

90

–

Round 2

Paediatric patients with CTX

Agreement

100

1

Round 2

In patients with CTX, the absence of dentate nuclei signal alteration in brain MRI may be an indicator of better prognosis

Agreement

75

2

Round 2

Increased atrophy and/or signal alteration, identified through brain MRI examinations, may be present in patients who have deteriorating neurological symptoms

Agreement

78

1

Round 2

Research indicates that treating CTX mothers with CDCA during pregnancy acts as an important means of protection against damage to the fetus and miscarriage

Consensus not reached

Agree (67) Disagree (0)

3

Round 3

Paediatric patients should undergo testing for urinary bile alcohol concentrations once per year

Consensus not reached

Agree (57) Disagree (14)

2

Round 3

Paediatric patients should undergo brain MRI at the time of diagnosis, then once per year during follow-up

Consensus not reached

Agree (11) Disagree (11)

–

Round 3

Disease progression in patients with CTX is better monitored using brain MRI compared with clinical evaluation alone

Consensus not reached

Agree (22) Disagree (44)

–

Round 3

CDCA alone is a preferred first line treatment compared to CDCA and HMG-CoA reductase inhibitor for treating the underlying biochemical abnormalities in CTX

Agreement

78

–

Round 3

There is a positive correlation between the progression of clinical and neuroradiological symptoms in patients with CTX

Consensus not reached

Agree (50) Disagree (0)

1

Round 3

Brain MRI can be used to determine neurological stability in patients with CTX

Consensus not reached

Agree (25) Disagree (25)

1

Round 3